FOCUS: An Open Label First in Human Phase I/II Multicentre Study to Evaluate the Safety, Dose Response and Efficacy of GT005 Administered as a Single Subretinal Injection in Subjects With Macular Atrophy Due to AMD
Phase: PHASE1
Conditions: Dry Age-related Macular Degeneration, Macular Degeneration, Retinal Disease, Eye Diseases, Retinal Degeneration, Geographic Atrophy, Macular Atrophy
Sponsor: Gyroscope Therapeutics Limited

Gyroscope Therapeutics 
GT005 
Confidential 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 1 of 144 
CONFIDENTIAL 
FOCUS: AN OPEN LABEL FIRST IN HUMAN PHASE I/II 
MULTICENTRE STUDY TO EVALUATE THE SAFETY, DOSE 
RESPONSE AND EFFICACY OF GT005 ADMINISTERED AS A 
SINGLE SUBRETINAL INJECTION IN SUBJECTS WITH MACULAR 
ATROPHY DUE TO AGE-RELATED MACULAR DEGENERATION 
PROTOCOL 
Version: 
Version date: 
Superseded versions: 
Sponsor: 
Product: 
Study Number(s): 
9.0 (Global Amendment) 
15 Dec 2022 
Version 8.0 (16 Feb 2022) 
Gyroscope Therapeutics 
GT005 
GT005-01/ NCT03846193
EudraCT number: 2017-003712-39 
Gyroscope Therapeutics Limited, 
Rolling Stock Yard, 
188 York Way, 
London, 
N7 9AS 
United Kingdom 
This protocol is the property of Gyroscope Therapeutics Ltd. It is not to be transmitted, 
copied or published without written permission from Gyroscope and must be kept in a 
confidential manner. Persons to whom the information is disclosed must be informed 
that the information is CONFIDENTIAL and may not be further disclosed by them. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 3 of 144 
 
AMENDMENT HISTORY 
Protocol 
Version 
Change 
Justification 
V1, 
04 DEC 2017 
Initial 
N/A 
V1.1, 
17 JAN 2018 
Alteration of Inclusion criteria 
Pregnancy test requirements 
Clarification of CFI assay 
Stopping rules amended 
CFP requirements amended. 
This amendment was created to 
address feedback from the 
MHRA. 
V2.0, 
18 SEP 2018 
This protocol amendment includes: 
New preclinical safety information 
has been provided 
Cohort 2 dose changed 
Inclusion criteria added for 
microperimetry sub—study 
Revised details of 
pharmacovigilance services. 
Emerging safety information. 
V3.0, 
02 MAY 2019 
This protocol amendment includes: 
Revision of entry criteria to:  
• 
include all eligible atrophic 
AMD patients: those with a 
rare variant resulting in CFI 
haploinsufficiency as well as 
those without a CFI variant. 
The requirement for low 
serum CFI has also been 
removed 
 
• 
Clarify microperimetry 
requirement. At sites with a 
MAIA MP, all subjects will be 
assessed with a MP if 
feasible as assessed by the 
Investigator 
GT005 has the potential to 
downregulate complement 
activation in all atrophic AMD, 
and there is no expectation that 
there would be differences in 
safety or tolerability in a broad 
atrophic AMD population; the two 
subpopulations will be analysed 
in the clinical endpoint analyses. 
 
As there are a limited number of 
subjects to evaluate the 
functional outcome of retinal 
sensitivity, this revision allows for 
inclusion of all subjects who may 
reasonably complete the 
assessment. 
Addition of a blood plasma sample 
collection at Dosing (Visit 2), 
Week 5 (Visit 4), Week 36 (Visit 7) 
or at Early Termination. 
 
 
 
 
 
Addition of microperimetry 
assessment at Week 12 (Visit 5) 
and at the Early Termination Visit. 
Due to the small sample size in 
the study, these additional 
assessments give opportunity to 
collect more microperimetry data. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 4 of 144 
 
Protocol 
Version 
Change 
Justification 
Amending the secondary endpoints 
to: 
Remove: 
• 
Change from baseline in 
retinal/drusen volume 
 
Include:  
• 
Anatomical measures of retinal 
microstructures via SD-OCT  
 
 
 
 
Drusen volume cannot currently 
be calculated via the Heidelberg 
Spectralis. 
 
Inadvertently missed. 
Administrative adjustment to 
bring in line with the protocol. 
Efficacy assessments: 
Removing the requirement to 
assess GA area size via CFP.  
 
CFP does not provide an 
accurate assessment of GA area 
size. Non-stereo images are 
sufficient to complete appropriate 
assessments. 
Correction of 
inconsistencies/inaccuracies. 
 
V4.0, 
03 SEP 2019 
This protocol amendment includes: 
• 
additional preclinical data 
supporting dose escalation 
to Cohort 3  
• 
an additional dose level 
(Cohort 3) and a dose 
expansion cohort (Cohort 4)  
 
 
 
 
• 
additional follow-up visits up 
to 4 years post-treatment 
 
 
Preclinical data update.  
 
Revised study design allows a 
more comprehensive evaluation 
of safety, dose response and 
efficacy of GT005 in subjects with 
GA due to AMD. 
 
 
 
 
 
 
 
 
The addition of a total follow-up 
period of 4 years post-treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 5 of 144 
 
Protocol 
Version 
Change 
Justification 
V5.0, 
27 JAN 2020 
This protocol amendment includes: 
• 
The addition of Cohorts 5 
and 6 where the delivery of 
GT005 will be via the Orbit 
SDS device. 
• 
Both eyes are required to be 
eligible for subjects 
considered for Cohorts 4 to 
6. The treated eye will be 
randomised for Cohorts 4 to 
6. 
• 
Inclusion of a baseline 
serum CFI sample  
• 
Correction of 
inconsistencies/inaccuracies  
 
The addition of Cohorts 5 and 6 
(Part 3) is designed to evaluate 
GT005 delivered with the Orbit 
SDS device.  
 
In cohorts 4 to 6, both eyes must 
be eligible to be enrolled into the 
study. The treatment eye will be 
determined by a randomization 
step to remove potential selection 
bias and provide a more robust 
assessment of GT005 therapy 
when compared to the untreated 
contralateral eye.  
 
Inclusion of a separate serum 
sample at baseline to determine 
serum CFI levels which will be 
analyzed at the central laboratory 
(Eurofins). 
V6.0/US, 
12 MAY 2020 
 
V6.0/UK, 
13 MAY 2020 
Schedule of Assessments. 
Screening period extended, 
incorporated a requirement for a 
pre-operative vision check if 
previous vision >4 weeks prior for 
patient safety and incorporated 
requirement of PRL identification 
pre-operatively. Clarified only 
related SAEs from time of 
consent, all AEs from time of 
randomization. 
Inclusion/Exclusion Criterion. 
Inclusion/exclusion criterion have 
been aligned with the Phase 2 
studies in order to ensure more 
consistent study populations. 
Clarification regarding performing 
and obtaining genotyping results 
prior to commencement of 
screening assessments. 
Given the low prevalence of CFI 
mutations and desire to minimize 
patient study activities, 
genotyping and serum CFI 
results will be received to confirm 
eligibility prior to other screening 
activities commencing. 
 
 
 
 
 
 
 
 
 
Additional Week 8 Visit added. 
 
To support additional safety 
monitoring, 
 
 
 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 6 of 144 
 
Protocol 
Version 
Change 
Justification 
 
 
 
 
 
 
 
 
 
 
Removed requirement to remain in 
medical facility overnight following 
surgery. 
 
Emerging safety profile from the 
completed dose escalation in 
Part 1 of the study does not 
support need for overnight stay in 
a medical facility. 
Risk Section updated. 
 
Updated risks to include those 
associated with topical steroid 
use. Added worsening of vision 
as a risk. 
 
 
 
  
Added (serious) adverse device 
effect language, device deficiency 
definitions and reporting 
requirements. 
Inclusion of Orbit SDS medical 
device for Cohort 5 and 6 
surgeries. 
Updated guidance on GT005 
destruction. 
Provide more detailed instruction 
and clarity. 
Throughout the document. 
 
Inconsistencies removed and 
language clarified. As these are 
minor revisions, they have not 
been summarised.  
V6.1/UK, 
17 NOV 2020 
Reference to the Orbit SDS medical 
device and Cohort 5-6 removed 
throughout protocol. 
Cohort 5 and 6 which includes 
delivery using the Orbit SDS 
device will not be conducted in 
the UK at this time. 
Remove reference to US region in 
protocol. 
Protocol amendment specific to 
UK. 
Extension of the duration of subject 
participation in study from 4 to 5 
years.  
Subject participation duration has 
been extended to 5 years to 
better characterise long-term 
outcomes following GT005 
treatment. 
Inclusion/Exclusion Criterion. 
Inclusion criterion 4 has been 
updated to ensure the subjects 
have GA lesion residing 
completely within the FAF fundus 
image for both eyes.  
 
New exclusion criterion 4 has 
been added to provide 
clarification on timing of cataract 
surgery prior to screening.  
 
Exclusion criterion 12 updated to 
clarify requirements for medical 
history of malignancies.  

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 7 of 144 
 
Protocol 
Version 
Change 
Justification 
Removal of randomisation step for 
Cohort 4. 
When AMD occurs bilaterally, the 
disease may progress within 
patients’ affected eyes at 
different rates. Central vision can 
be impacted non-uniformly 
across both eyes of the same 
patient, therefore resulting in a 
‘better seeing’, or ‘preferred’ eye.  
 
Randomization of treatment eye 
was introduced in protocol v5.0 to 
minimize potential selection bias. 
However, on further review and 
feedback from study 
investigator(s), it is deemed more 
appropriate that the eye with the 
worse vision is selected by 
default, rather than using a 
randomisation method that may 
give rise to the better seeing eye 
being selected for surgery, 
particularly for an early phase 
clinical study with a less 
characterised safety profile.  
 
Randomisation of the patient's 
eye within Cohort 4 has therefore 
been removed. 
 
 
 
 
 
 
 
Clarification of OCT modalities.  
The differing OCT modalities 
have been clarified: OCT macula 
 to provide clarity to 
investigational sites and to add 
further timepoints if required by 
the Investigator to detect any 
safety changes on the retina, 
i.e. 
 any other 
safety-related changes.  
Include additional timepoints for 
collecting colour fundus photos and 
OCT imaging post-treatment. 
Timepoints added to better 
characterise any anatomical or 
safety-related ocular changes 
post GT005 treatment.  

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 8 of 144 
 
Protocol 
Version 
Change 
Justification 
Screening and eligibility 
requirements for subjects. 
To prevent repeating screening 
visits and all assessments more 
than once, data from subjects 
screened in another Gyroscope 
sponsored study, conducted at 
the same Investigative site as the 
FOCUS study, may be used to 
fulfil the screening and eligibility 
requirements for this study if they 
were performed within the study 
screening period. 
 
 
AE Reporting language. 
Safety reporting requirements 
updated to collect all AEs from 
date of consent.  
Throughout the protocol. 
Administrative 
inconsistences removed and 
language clarified. As these are 
minor revisions, they have not 
been summarised. 
V7.0/US, 
01 DEC 2020 
Addition of a dose-expansion 
Cohort 7. 
 
Increase in number of total subjects 
enrolled in study from 45 to 65. 
 
Revised study design allows a 
more comprehensive evaluation 
of safety, dose response and 
efficacy of GT005, when 
administered using Orbit SDS 
device in subjects with GA due to 
AMD. 
Increase in overall study enrolment 
by 3.5 months. 
 
To accommodate the enrolment 
of an additional to subjects in 
Cohort 7. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 9 of 144 
 
Protocol 
Version 
Change 
Justification 
Removal of randomization step for 
Cohort 4-6. 
When AMD occurs bilaterally, the 
disease may progress within 
patients’ affected eyes at 
different rates. Central vision can 
be impacted non-uniformly 
across both eyes of the same 
patient, therefore resulting in a 
‘better seeing’, or ‘preferred’ eye.  
 
Randomization of treatment eye 
was introduced in protocol v5.0 to 
minimize potential selection bias. 
However, on further review and 
feedback from study 
investigator(s), it is deemed more 
appropriate that the eye with the 
worse vision is selected by 
default, rather than using a 
randomization method. A 
randomization method may give 
rise to the better seeing eye 
being selected for surgery, 
particularly for an early phase 
clinical study with a less 
characterised safety profile.  
 
Randomization of the subjects’ 
eye within Cohort 4-6 has 
therefore been removed. 
Addition of OCT-A and FA. 
OCT-A imaging added, if 
required, to identify potential 
CNV conversion during the study. 
 
FA included as an assessment to 
verify subjects do not have CNV 
at baseline or conversion to CNV 
during the study. 
Removal of reference to PRL 
identification prior to surgery. 
 
Requirements surrounding PRL 
identification are described in the 
surgical manual.  
Extension of the duration of subject 
participation in study from 4 to 
5 years.  
Subject participation duration has 
been extended to 5 years to 
better characterize long-term 
outcomes following GT005 
treatment. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 10 of 144 
 
Protocol 
Version 
Change 
Justification 
Inclusion/Exclusion Criterion 
(Cohort 4 to 7 only). 
Inclusion criterion 4 has been 
updated to ensure the subjects 
have GA lesion residing 
completely within the FAF fundus 
image for both eyes.  
 
Inclusion criterion 5 broadened to 
BCVA of 24 letters (6/95 and 
20/320 Snellen acuity 
equivalent), to allow inclusion of 
subjects with worse-seeing vision 
who may benefit from GT005 
treatment.  
 
New exclusion criterion 4 has 
been added to provide 
clarification on timing of cataract 
surgery prior to screening.  
 
Exclusion criterion 12 updated to 
clarify requirements for medical 
history of malignancies.  
Amending the secondary endpoints 
to include:  
• 
To evaluate the performance of 
the Orbit SDS 
• 
To evaluate the safety of the 
Orbit SDS 
Device-related endpoints added 
to more robustly characterize the 
performance and safety of the 
Orbit SDS.  
 
 
 
 
 
 
 
 
Clarification of OCT modalities.  
The differing OCT modalities 
have been clarified: OCT macula 
 to provide clarity to 
investigational sites and to add 
further timepoints if required by 
the Investigator to detect any 
safety changes on the retina, i.e., 
 any other 
safety-related changes.  
Include additional timepoints for 
collecting colour fundus photos and 
OCT imaging post-treatment. 
Timepoints added to better 
characterize any anatomical or 
safety-related ocular changes 
post GT005 treatment. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 11 of 144 
 
Protocol 
Version 
Change 
Justification 
Screening and eligibility 
requirements for subjects. 
To prevent repeating screening 
visits and all assessments more 
than once, data from subjects 
screened in another Gyroscope 
sponsored study, conducted at 
the same Investigative site as the 
FOCUS study, may be used to 
fulfil the screening and eligibility 
requirements for this study if they 
were performed within the study 
screening period. 
 
 
AE Reporting language. 
Safety reporting requirements 
updated to collect all AEs from 
date of consent. 
Throughout the protocol. 
Administrative 
inconsistencies removed and 
language clarified. As these are 
minor revisions, they have not 
been summarised. 
V7.1 (US), 
30 MAR 2021 
Clarify the window for conduct of the 
pre-operative study assessments.  
Administrative inconsistencies 
between different protocol 
sections corrected and language 
clarified. 
Removal of the requirement for the 
blood pressure assessment to be 
conducted on the same arm 
throughout the study. 
 
The blood pressure assessment 
may be conducted on either arm 
as there is no scientific 
requirement, under the context of 
this study, for blood pressure be 
collected on the same arm 
throughout the study. 
Removal of the requirement for 
OCT-A certification. 
 
OCT-A certification requirements 
will be defined in the FOCUS 
Imaging Manual instead of the 
protocol. 
Removal of specified requirements 
for the Microperimetry assessment.  
 
Microperimetry instructions will 
be provided in the imaging 
manual.  
In line with the clinical standard of 
care, CNV assessment may be 
performed in a step-wise manner 
with an initial evaluation made on 
the OCT and/or OCT-A images by 
the Central Reading Centre. In the 
event, that the OCT/OCT-A images 
are inconclusive to rule out the 
presence of CNV the subject will be 
required to undergo an additional 
assessment via FA. 
Added clarification to the CNV 
assessment process to ensure 
alignment with clinical standard 
of care. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 12 of 144 
 
Protocol 
Version 
Change 
Justification 
V8.0 
(Global), 
16 FEB 2022 
Changes 
from 
V7.1 (US), 
30 MAR 2021 
and/or 
V6.1 (UK), 
17 NOV 2020 
US- and UK-specific protocols 
combined into a single global 
protocol. Unless specified, the 
changes detailed below apply to the 
amendment of both protocols. 
To have a single global protocol. 
Clarification of the study design for 
the different treatment Cohorts 
between US and UK. 
Provided clarity on the use of the 
Orbit SDS device in the US only 
for GT005 delivery for cohorts 5-
7, as 510(k) cleared in the US.  
Specifically for the amendment of 
the UK protocol v6.1: The Orbit SDS 
and suprachoroidal cannulation are 
described, Cohorts 5-7 are included, 
and the study details for these 
cohorts are included. These 
changes are applied throughout the 
protocol (Synopsis, Section 1, 
Section 3, Section 6). 
The US- and UK-specific 
protocols have been combined 
into a single global protocol. The 
Orbit SDS device will only be 
used in the US in cohorts 5-7 and 
was not included in the UK 
protocol v6.1. 
Specifically for the amendment of 
the UK protocol v6.1: update to the 
number of subjects to include the 
US-specific cohorts. 
Update to number of subjects 
since Cohorts 5-7 only recruit 
subjects in the US and were not 
included in the UK protocol v6.1. 
Increase in number of study sites 
after combining US- and UK-specific 
protocols. 
Specifically for the amendment of 
the UK protocol v6.1: The 
number of study sites increased 
to accommodate additional 
cohorts in the study from 10 
sites, in up to 20 sites. 
 
Specifically for the amendment of 
the US protocol v7.1: The 
number of study sites increased 
to accommodate additional 
subjects in the study from 12 
sites, in up to 20 sites. 
Study duration clarified, excluding, 
the recruitment duration. 
Clarified the total study length 
post-treatment follow-up period is 
5 years only and removed 
additional text relating to study 
recruitment.  
Provided further details of the 
screening assessments that should 
be repeated if the screening period 
is extended past the original 8-week 
screening period (8-12 weeks). 
Provided clarification that if the 
screening period is extended to 
8-12 weeks, the site staff need to 
repeat only the standard 
ophthalmic exam, 
haematology/biochemistry and 
visual acuity (BCVA and LLVA). 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 13 of 144 
 
Protocol 
Version 
Change 
Justification 
Extension of the 8-week screening 
period up to 16 weeks in the event 
of GT005 deferral during surgery. 
Clarified that in the event GT005 
dosing was deferred during 
surgery, the time from screening 
may be extended up to 16-weeks 
Clarified that if the time from 
screening is extended past 12 
weeks, in case of GT005 
deferral, FAFs should be 
repeated in addition to the 
standard ophthalmic exam, 
haematology/biochemistry and 
BCVA/LLVA. 
Update to AE monitoring to allow for 
additional assessment.  
Clarified that additional imaging 
or functional assessments may 
be conducted, as needed, to 
allow for safety assessment. 
 
 
 
 
 
 
 
 
  

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 14 of 144 
 
Protocol 
Version 
Change 
Justification 
Consolidation and expansion of the 
objectives and evaluation criteria. 
 
 
 
 
Reduced the number of primary 
objective evaluation criteria. 
 
 
 
 
Update to the evaluation criteria for 
the secondary objective to evaluate 
the effect of GT005 on anatomical 
and functional visual outcomes. 
 
 
 
 
Update to secondary objectives for 
the Orbit SDS cohort in the US only.  
 
 
 
 
 
 
 
 
 
 
To include the objectives and 
evaluation criteria from both the 
US- and UK-specific protocols, 
and to further define the 
objectives and evaluation criteria. 
 
Updated to report the main 
primary objective/evaluation 
criteria assessed and clarified 
that the endpoint will be 
evaluated over 48 weeks. 
 
Moved criteria on BCVA from the 
primary evaluation criteria to be 
reported as a secondary 
objective in the study. Added that 
the endpoints will be evaluated 
over 48 weeks. 
 
 
Updated to include the specific 
endpoint and not the 
performance target. 
 
 
 
 
 
 
 
 
 
 
 
  
Inclusion/Exclusion Criteria. 
To broaden and provide further 
clarity on the study eligibility 
criteria: 
 
Inclusion criterion 2 has been 
revised to include a broader 
population of patients with GA 
(unilateral or bilateral), with a 
requirement of AMD in the 
contralateral eye (except if the 
subject is monocular), but no 
requirement of GA in the fellow 
eye. 
 
Inclusion criterion 3 has been 
revised to allow GA lesion total 
size in the study eye ≥1.25mm2 
with no upper limit in Cohort 7 
only. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 15 of 144 
 
Protocol 
Version 
Change 
Justification 
 
Inclusion criterion 3 and 
criterion 4 have been revised to 
remove the requirement related 
to the GA lesion in the fellow eye 
in Cohorts 4 to 7. 
 
Inclusion criterion 5 has been 
revised to remove the BCVA 
requirement for the fellow eye in 
Cohorts 4 to 7. 
 
Exclusion criterion 1 has been 
revised to allow inclusion of 
subjects with CNV in the fellow 
eye (given specific criteria). 
 
Exclusion criteria 2, 3, 5, 6, and 7 
have been revised to apply 
criteria to the study eye only, to 
broaden inclusion of subjects into 
the study. 
Specifically for the amendment of 
the UK protocol v6.1: 
Inclusion/Exclusion Criteria. 
Inclusion criterion 5 broadened to 
BCVA of 24 letters (6/95 and 
20/320 Snellen acuity equivalent) 
for Cohorts 4 to 7, to allow 
inclusion of subjects with worse-
seeing vision who may benefit 
from GT005 treatment. This 
inclusion criterion was previously 
broadened in the US protocol 
v7.1, but not the UK protocol 
v6.1. 
 
Exclusion criterion 14 added. 
This criterion applies to the 
US-specific cohorts, so was not 
included in the UK protocol v6.1. 
Options to perform the visual acuity 
check pre-surgery.  
Provided clarification on the 
possibility to use ETDRS (not 
only Snellen) for pre-surgery 
visual acuity check. 
Specifically for the amendment of 
the UK protocol v6.1: OCT-A 
imaging added, if required, to 
identify potential CNV conversion 
during the study. OCT-A 
methodology included. 
The US- and UK-specific 
protocols have been combined 
into a single global protocol. This 
change was previously made in 
the US protocol v7.1, but not in 
the UK protocol v6.1. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 16 of 144 
 
Protocol 
Version 
Change 
Justification 
Specifically for the amendment of 
the UK protocol v6.1: Removal of 
reference to PRL identification prior 
to surgery (requirements 
surrounding PRL identification are 
described in the surgical manual). 
The US- and UK-specific 
protocols have been combined 
into a single global protocol. This 
change was previously made in 
the US protocol v7.1, but not in 
the UK protocol v6.1. 
Removal of reference to a “central” 
surgical site. 
Clarification of terminology that 
subjects will undergo subretinal 
surgery at the study site. 
Removal of text describing 
procedures for destruction of GT005 
This information will be included 
within the pharmacy manual 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Risk/benefit analysis update to 
include that GT005 is in early 
clinical development.  
 
Clarified that the potential risks of 
GT005 have also been evaluated 
in preliminary clinical data (in 
humans). 
Update to reason for screen failure.  
 
Clarified that eligible subjects 
who do not receive treatment, 
can be replaced and classed as 
screen failures. 
Update of the list of options for 
action taken regarding study drug in 
the adverse event reporting section. 
To more accurately document 
this information. 
Update of the device malfunction 
definition. 
For clarification. 
Specifically for the amendment of 
the UK protocol v6.1: inclusion of 
definition and reporting of device 
specific AEs, and a section on 
device malfunctions. 
The US- and UK-specific 
protocols have been combined 
into a single global protocol. 
There was no device-related 
information in the UK protocol 
v6.1. 
Update to clarify the statistical 
methods and analysis. 
 
 
Update to define the Safety Set and 
Full Analysis Set. 
To more fully describe the 
planned statistical analyses by 
dose, route of administration and 
for both eyes. 
 
Clarified that the Safety Set (SS) 
will be used for analysis of safety 
and laboratory data. 
The Full Analysis Set will include 
all subjects in SS who have 
baseline and at least one 
post-baseline value of GA area 
size via FAF in the study eye. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 17 of 144 
 
Protocol 
Version 
Change 
Justification 
A more detailed description of the 
role of the IRB/REC and Competent 
Authority is included. 
Alignment of the US- and UK-
specific protocols to combine into 
a single global protocol. 
DSMB meeting schedule update.  
Clarification that additional DSMB 
meetings can be held as needed 
or at the request of the DSMB 
members. 
GT005 will be labelled in 
accordance with specific local 
requirements. 
The US- and UK-specific 
protocols have been combined 
into a single global protocol, 
therefore, clarified that labelling 
of GT005 with occur in line local 
requirements.  
Orbit SDS (US only) regulatory 
guidance on labelling. 
Clarification labelling will be in 
accordance with FDA regulations 
for marketed products only. 
Schedule of events updated in line 
with changes in the protocol. 
For consistency. 
 
Genetic testing and confidentiality of 
trial documents and subject records 
updated. 
Updated to include that the 
distribution of genetic data is 
carefully controlled.  
Administrative changes throughout 
the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administrative inconsistencies 
removed, and language clarified 
in the study design figure and 
throughout the protocol. As these 
are minor revisions, they have 
not been summarised. 
 
For consistency with other clinical 
protocols, updated the term 
macular atrophy to geographic 
atrophy, secondary to AMD. 
 
For consistency, low dose, 
 
 
 have been defined, where 
appropriate. 
 
Update to change in Sponsor 
address. 
 
For consistency, updated the 
Transvitreal Surgical Procedure 
Manual and Orbit SDS Surgical 
Procedure Manual to relevant 
Surgical Manual.  
 
Alignment of the protocol 
signature page to global 
protocols. 

Gyroscope Therapeutics 
GT005 
 
Confidential 
 
Protocol Amendment 9: GT005-01 
Version: 9.0 (Global) 
Date: 15 Dec 2022  
Page 18 of 144 
 
Protocol 
Version 
Change 
Justification 
V9.0 
(Global), 15 
Dec 2022 
Changes 
from V8.0 
(Global) 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Updated the Synopsis and Section 
2 Study Objectives to:  
• 
Evaluate long-term safety of 
GT005 at 3 doses (in up to 240 
Weeks) 
• 
Clarify secondary and 
 endpoints to be 
reported through Week 240 
• 
Included a new secondary 
objective and report the long-
term safety of GT005 until the 
end of study  
• 
Clarified the analysis 
timepoints for secondary and 
 endpoints to be 
reported until the end of study  
• 
Updated recent information 
under Section 1.6.1.1, ‘Risks 
associated with GT005’ 
• 
This section has been aligned 
with the current version of the 
Investigator’s Brochure (IB) 
• 
Clarification to Section 11.3.2 
Statistical Analysis, Efficacy that 
Interim analyses may be 
considered  
• 
To help inform internal 
development decision points 
for GT005. Details will be pre-
specified in the SAP prior to 
conducting the analysis 
• 
Added Section 8.2.4, footnote 
15 (Table 2) and footnote 9 
(Table 3) in the Schedule of 
Assessments to include the 
submission of historical FAF and 
OCT images by the sites  
• 
To obtain individual historical 
information on natural GA 
disease progression prior to 
enrolment and treatment in 
the study, for potential data 
sub analyses   
• 
Updated Section 7 Study Plan 
and Footnote 1 (Table 1, Table 
2, Table 3) in the Schedule of 
Assessments to include 
definition of the Surgical Site  
 
• 
To optimise operational 
management of the study and 
clarify where the study 
assessments can be 
conducted, the definition of 
surgical site has been 
included  

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Protocol 
Version 
Change 
Justification 
Updated Section 7.8, Section 7.10, 
Section 7.13, Section 7.14, Section 
7.15, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
For consistency with other 
clinical protocols and to 
prevent sampling error 
• 
Update to the Schedule of 
Assessments, OCT-A and FA. 
In Table 2, Footnote 8 and 
Table 3, Footnote 4 were added 
to follow-up visits, to clarify that 
OCT-A and/or FA may be 
performed if clinically indicated 
during follow-up 
• 
The Schedule of 
Assessments has been 
aligned with the main body of 
the protocol under Section 7 
for consistency 
• 
Added Section 7.18.2 for Post 
Week 48 Early Termination 
assessments and updated the 
Early Termination Visit 
Scheduled Assessments to 
overlap with the Unscheduled 
Visit Assessments for Table 3  
• 
To clarify Early Termination 
procedures, post week 48 
during the long term follow-up 
study visits  
• 
Updated Section 8.2.3, 
 
 footnote 14 (Table 2) 
and footnote 5 (Table 3) to 
clarify that simultaneous 
binocular testing is not required 
in this study 
• 
To provide guidance on the 
assessments required for 
 
• 
Updated Section 6.9 Drug and 
Surgical Device Accountability to 
include that devices should be 
returned upon the end of study 
enrolment instead of at the end 
of study 
• 
Further clarity on return of 
surgical devices has been 
provided 
 
• 
Removal of Steering Committee 
from the Synopsis and Section 
24  
• 
Removed reference to this 
study-specific steering 
committee that is no longer in 
place, and has been 
superseded by other sponsor 
scientific and clinical advisory 
boards  

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Protocol 
Version 
Change 
Justification 
• 
Administrative Changes 
• 
Update to Sponsor Name on 
Title page since Gyroscope 
was acquired by Novartis in 
February 2022 
 
• 
Clarification to Synopsis and 
Section 3 Study Design, 
Figure 1 titled “Overview of 
the Study Design (Parts 3 
and 4 are US Only)” for 
Cohort 7 to state n=up to 20, 
as per the main body of the 
protocol 
 
• 
For general document 
improvement, providing 
further clarity where 
necessary and following input 
from sites/regulators and 
other stakeholders, ensuring 
consistency, addressing 
inadvertent formatting and 
typographical errors from the 
last version 
 
 
• 
Update to footer enumeration 
on Table 1, Table 2, and 
Table 3 as re-enumeration 
was required as a result of 
updating SOA footers to 
incorporate the changes 
identified in this table 
 
• 
Updated term Statistical Set 
to Statistical Analysis Set and 
corresponding abbreviation 
SS to SAF 
Abbreviations: AEs=adverse events; AESI=adverse events of special interest; AMD=age-related macular 
degeneration; BCVA=best corrected visual acuity; CFI=complement factor I; CFP=colour fundus photography; 
CNV=choroidal neovascularisation; COVID-19=Coronavirus Disease 2019; DSMB=data safety monitoring 
Board; FA=Fluorescein angiography; FAF=fundus autofluorescence; GA=geographic atrophy (also known as 
macular atrophy); FAS=full analysis set; MAIA=macular integrity assessment; MHRA=Medicines and Healthcare 
products Regulatory Agency; MP=microperimeter; N/A=not applicable; OCT=Optical coherence tomography; 
OCT-A=optical coherence tomography angiography; PRL=preferred retinal locus; SAE=serious adverse event; 
SD-OCT=spectral domain optical coherence tomography; SDS=subretinal delivery system; SAF=safety analysis 
set; V=version; 
. 

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PROTOCOL SYNOPSIS 
TITLE: 
FOCUS: An open label first in human Phase I/II multicentre study to evaluate the 
safety, dose response and efficacy of GT005 administered as a single subretinal 
injection in subjects with macular atrophy due to age-related macular degeneration 
PROTOCOL NO: 
GT005-01 
INVESTIGATOR STUDY SITES: 
All subjects will undergo subretinal surgery at a surgical site. Subject recruitment 
and most follow-up visits will be conducted in up to 20 study sites (including the 
surgical sites). 
STUDY PERIOD: 
Total study length is estimated to be 5-years post-treatment follow-up period. 
OBJECTIVES: 
The overall objectives of the study are to evaluate the safety, the dose response 
and efficacy (anatomical and functional visual outcomes) of three doses of GT005 
in subjects with geographic atrophy (GA, also known as macular atrophy) due to 
age-related macular degeneration (AMD) when delivered subretinally via the 
transvitreal procedure or suprachoroidal cannulation.  
INVESTIGATIONAL MEDICINAL PRODUCT: 
Name and Description of GT005: 
A recombinant adeno-associated virus vector (AAV) derived from wild-type AAV 
serotype 2 (AAV2). The expression cassette contains deoxyribonucleic acid 
encoding for human complement factor I (hCFI). 
METHODOLOGY: 
This is an open label first in human Phase I/II multicentre study to evaluate the 
safety, dose response and efficacy of GT005 in subjects with GA due to AMD. The 
study will be conducted in four parts; Part 1 (Cohorts 1 to 3): dose-escalation, Part 2 
(Cohort 4): dose-expansion, Part 3 (Cohorts 5 to 6): dose-escalation with the Orbit 
Subretinal Delivery System (SDS), and Part 4 (Cohort 7): dose-expansion with the 
Orbit SDS.  
Parts 1 and 2 (Cohorts 1 to 4) will deliver GT005 via the standard transvitreal 
procedure and Parts 3 and 4 (Cohorts 5 to 7) will deliver GT005 via the Orbit SDS.  
The Orbit SDS is a 510(k) cleared device in the United States (US) whereby Parts 
3 and 4 (Cohorts 5 to 7) will only be used at US sites.  
Part 1 (Cohorts 1 to 3; dose-escalation) will test three dose cohorts (low dose, 
; 
vector genomes [vg]) of up to five subjects 
per cohort. Sentinel dosing will be applied whereby there will be a minimum of 14 
days separation between dosing of the first and second subject of each dose cohort, 
to assess any acute reactions to surgery and the short-term tolerability to GT005 
prior to dosing the remaining subjects in each dose cohort. Dose-escalation will be 
evaluated by a Data Safety Monitoring Board (DSMB) and will be assessed based 
on the Week 5 safety data for the first three subjects dosed in each of Cohorts 1 and 

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2. The DSMB will review the Week 5 safety data for the first three subjects dosed in 
Cohort 3 prior to dosing in further cohorts. 
Subjects will receive a single subretinal injection of GT005 at one of three dose 
levels:  
• 
 AAV2 vg in 100 microlitres  
• 
 AAV2 vg in 100 microlitres 
• 
 AAV2 vg in 100 microlitres 
Part 2 (Cohort 4; dose-expansion) will enrol up to 20 subjects in Cohort 4 with GT005 
delivered via the transvitreal procedure to further characterise the safety, dose 
response, and efficacy of GT005. On completion of dose-escalation, dose levels 
determined to be safe and tolerable by the DSMB in Part 1 (Cohorts 1 to 3), may be 
assessed in Cohort 4. The exact number of subjects that will be enrolled in Cohort 
4 will be determined by the Sponsor based on the emerging safety, 
pharmacodynamic and clinical outcomes data.  
Part 3 (Cohorts 5 to 6; dose-escalation and evaluation of two doses of GT005 
delivered with the Orbit SDS; subretinal delivery via a suprachoroidal cannulation) 
will enrol three to five subjects at the mid dose (
 vg; Cohort 5) and three to five 
subjects at the high dose (
 vg; Cohort 6), to evaluate the safety of GT005 
treatment when delivered via the Orbit SDS. Part 3 (Cohorts 5 to 6) is independent 
of, and may be conducted in parallel to, Part 2 (Cohort 4). Dose-escalation will be 
evaluated by the DSMB and will be assessed based on the Week 5 safety data for 
the first three subjects dosed in Cohort 5.  
Part 4 (Cohort 7) dose-expansion of GT005 delivered with the Orbit SDS; subretinal 
delivery via a suprachoroidal cannulation) will enrol up to 20 subjects in Cohort 7 to 
further characterise the safety, dose response, and efficacy of GT005 treatment 
when delivered via the Orbit SDS. On completion of dose-escalation, dose levels 
determined to be safe and tolerable by the DSMB in Part 1 (Cohorts 1 to 3) may be 
assessed in Cohort 7. The exact number of subjects that will be enrolled in Cohort 7 
will be determined by the Sponsor based on the emerging safety, pharmacodynamic 
and clinical outcomes data.  
The study treatment consists of an AAV2 expressing hCFI. The treatment is 
administered as a single subretinal injection into one eye – “the study eye”. Both 
eyes will be assessed at the screening visit. If both eyes meet the eligibility criteria 
the study eye will be the worse seeing eye or the eye with the largest GA size for 
eyes with equivalent visual acuity unless the patient (in consultation with the 
surgeon) expresses an alternative preference.  
The study will, for the individual subjects, consist of up to 13 visits over a 5-year 
period. All subjects will be assessed for the occurrence of adverse events (AEs) at 
each visit and will undergo functional visual and retinal imaging/anatomical 
assessments and biological sampling as per the schedule of assessments. 
 
 
 
 

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Objectives 
Evaluation Criteria 
Primary 
• To evaluate the safety of 
GT005 at 3 doses  
• Incidence of ocular and non-ocular treatment-
emergent AEs (TEAEs) and treatment-emergent 
serious AEs (TESAEs) over 48 weeks 
Secondary 
• To evaluate long-term 
safety of GT005 at 3 
doses 
• Incidence of ocular and non-ocular treatment-
emergent AEs (TEAEs) and treatment-emergent 
serious AEs (TESAEs) up to 240 weeks 
• To evaluate the effect of 
GT005 on anatomical 
and functional visual 
outcomes 
• Best corrected visual acuity (BCVA) and low 
luminance visual acuity (LLVA) score via the 
early treatment diabetic retinopathy study 
(ETDRS) chart up to 240 weeks  
• Macular sensitivity as assessed by Mesopic 
Microperimetry up to 240 weeks  
• Change in GA area size as assessed by fundus 
autofluorescence (FAF) up to 240 weeks 
• To evaluate the 
performance of the Orbit 
SDS (US only) 
• Rate of successful delivery of balanced salt 
solution (BSS) or BSS PLUS to the subretinal 
space 
• Rate of successful delivery of GT005 to the 
subretinal space 
• To evaluate the safety of 
the Orbit SDS (US only) 
• Incidence of device-related AEs and SAEs 
 
• 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
• 
 
 
• 
 
 
 
 
• 
 
 
 

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• 
 
 
 
Following consent, subjects will undergo several ophthalmic and clinical 
assessments to determine eligibility for inclusion in the study. Once eligibility is 
confirmed by the Sponsor the subject will be enrolled. The subject will be scheduled 
for surgery 
 
 
 
Subretinal surgery and administration of GT005 will take place at a surgical site. 
 
.
 
 
  
During surgery, 
 
 
 The surgery will be performed under local 
anaesthesia. Other anaesthetic options will be considered by the surgeon as 
appropriate for the subject. Then subjects will receive GT005 at one of the three 
doses (
) as a single administration in the form of a 
subretinal injection of 100 microlitres. After surgery, subjects will remain in the clinic 
for up to 24 hours following the surgery to assess any acute issues resulting from 
the surgery. 
 
 
Subjects will undergo follow-up visits at Week 1, 5 and 8 post-dosing, every three 
months post-dosing (at Weeks 12, 24, 36, and 48) for the first year, and at Weeks 72 
(1.5 years), 96 (2 years), 144 (3 years), 192 (4 years), and 240 (5 years) 
post-dosing. At the Week 48 visit, subjects will be invited to consent to the additional 
follow-up (up to and including Week 240 visit). The Week 48 visit will be the time 
point used for the primary endpoint of the study. Week 240 (Year 5) will be the end 
of the study. 
NUMBER OF SUBJECTS: 
Approximately 65 subjects will be enrolled: up to five in each of Cohorts 1 to 3, up 
to 20 in Cohort 4, up to five in each of Cohorts 5 and 6, and up to 20 in Cohort 7.  
Subjects who are screened but do not receive treatment, will be classed as screen 
failures and may be replaced. The 8-week screening period may be extended up 
to 12 weeks if agreed by the Sponsor Medical Monitor. If the screening period is 
extended past the original 8-week screening period (8–12 weeks), standard 
ophthalmic exam, haematology/biochemistry, and visual acuity (BCVA/LLVA) 
assessments should be repeated. In the event the GT005 administration is 
deferred during the surgical procedure (e.g., due to an AE occurring during 
surgery) the screening period may be extended up to 16 weeks if agreed by the 
Sponsor Medical Monitor. Additionally, if the screening period is extended past 12 
weeks (12–16 weeks), in case of GT005 deferral, standard ophthalmic exam, 
haematology/biochemistry, visual acuity (BCVA/LLVA), and FAFs will be repeated. 
In the event, that a subject withdraws from the study for any reason other than an 
AE or other safety concern or is lost to follow-up within 6 months (Week 24) post 

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dosing, the subject may be replaced. The reason for the subject’s withdrawal from 
the study must be recorded. 
INCLUSION/EXCLUSION CRITERIA: 
Inclusion Criteria: 
1. Able and willing to give consent to study participation 
2. Have a clinical diagnosis of GA secondary to AMD in the study eye, as 
determined by the Investigator, and a diagnosis of AMD in the contralateral 
eye (except if the subject is monocular)  
3. Cohorts 1 to 6: GA lesion(s) total size in the study eye must be ≥1.25mm2 
and ≤17.5mm2 
Cohort 7: GA lesion(s) total size in the study eye must be ≥1.25mm2 
4. GA lesion(s) in the study eye must reside completely within the FAF fundus 
image 
5. Cohorts 1 to 3: BCVA of ≤50 letters (6/36 Snellen acuity equivalent or 
worse) using ETDRS charts in the study eye 
Cohorts 4 to 7: BCVA of ≥24 letters (6/95 and 20/320 Snellen acuity 
equivalent or better) using ETDRS charts in the study eye  
6. Aged ≥55 years 
7. Able to attend all study visits and complete the study procedures 
8. Women of child-bearing potential need to have a negative urine pregnancy 
test within two weeks prior to receiving the drug. A pregnancy test is not 
required for postmenopausal women (defined as being at least 
12 consecutive months without menses) or those surgically sterilised (those 
having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal 
occlusive procedure, hysterectomy, or bilateral oophorectomy) 
Exclusion Criteria: 
1. Have evidence or history of choroidal neovascularisation (CNV) in the study 
eye. Subjects are permitted to have CNV in the fellow eye defined as either: 
a. Non-exudative/sub-clinical fellow eye CNV identified at screening, or 
b. Known history of fellow eye CNV with either ≥2 years since diagnosis or 
with no active treatment required in 6 months prior to screening 
2. Presence of moderate/severe non-proliferative diabetic retinopathy or worse 
in the study eye 
3. Have history of vitrectomy, sub-macular surgery, or macular 
photocoagulation in the study eye 
4. History of intraocular surgery in the study eye within 12 weeks prior to 
Screening (Visit 1). 
 
 
5. Have clinically significant cataract that may require surgery during the study 
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6. Presence of moderate to severe glaucomatous optic neuropathy in the 
study eye; uncontrolled intraocular pressure (IOP) despite the use of more 
than two topical agents; a history of glaucoma-filtering or valve surgery is 
also excluded 
7. Axial myopia of greater than -8 diopters in the study eye 
8. Have received any investigational product for the treatment of GA within the 
past 6 months or 5 half-lives (whichever is longer), other than nutritional 
supplements such as the age-related eye disease study (AREDS) formula 
9. Have received a gene or cell therapy at any time 
10. Have a contraindication to the specified protocol corticosteroid regimen 
11. Are unwilling to use two forms of contraception (one of which being a barrier 
method) for 90 days post-dosing, if relevant 
12. Active malignancy within the past 12 months, except for: Appropriately 
treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or 
prostate cancer with a stable prostate-specific antigen (PSA) ≥12 months 
13. Have any other significant ocular or non-ocular medical or psychiatric 
condition which, in the opinion of the Investigator, may either put the subject 
at risk or may influence the results of the study 
14. Cohorts 5 to 7 only: presence of metallic objects or implanted stimulator 
devices in or near the head, including cochlear implants, deep brain 
stimulators, vagus nerve stimulators, and other implanted electrodes or 
stimulators 
DOSE/ROUTE/REGIMEN: 
The study drug is supplied to the surgical site as a vial of frozen sterile liquid. 
GT005 is an aqueous suspension of recombinant AAV2 vector particles in 
 
 
 GT005 is administered at ambient temperature as a single subretinal 
injection into the macula of the study eye. 
Surgical procedure 
GT005 will be administered subretinally via the transvitreal procedure for Cohorts 1 
to 4, an approach which is based on publicly available methodology. GT005 will be 
administered subretinally via a suprachoroidal cannulation with the Orbit SDS for 
Cohorts 5 to 7 (US sites only). All Cohorts will be treated by an appropriately 
qualified vitreoretinal surgeon in an operating room under local anaesthesia. Other 
anaesthetic options will be considered by the surgeon as appropriate for the subject. 
The total duration of the surgery is about 1 hour. The detailed procedure is described 
in the relevant Surgical Manuals. 
In brief: 
Cohorts 1 to 4 
 
 
 
 
 

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Cohorts 5 to 7 (US sites only) 
 
 
 
 
 
DURATION OF TREATMENT AND FOLLOW-UP 
Subjects will receive a single subretinal injection and will be followed for up to 
240 weeks (5 years) post-dosing.  
REFERENCE TREATMENT: 
Only one eye will be treated in the study and the untreated fellow eye will be the 
comparator.  
The eye with the worse visual acuity will be the study eye. If visual acuity is 
equivalent in both eyes, the eye with the largest area of GA will be the study eye 
unless the patient (in consultation with the surgeon) expresses an alternative 
preference. The study eye will be confirmed by the vitreoretinal surgeon.  
STATISTICAL METHODS: All the efficacy data (anatomical and functional visual 
outcomes),
 and 
 data and safety data 
(including laboratory safety) collected will be amalgamated into a single database 
with datasets constructed according to these categories. Unless otherwise stated, 
data will be summarised in aggregate by dose and route of administration. Further 
detail will be described in the statistical analysis plan. 
Analysis Set 
Two analysis sets will be defined. The Safety Analysis Set (SAF) will include all 
subjects who have undergone surgery and received GT005. The SAF will be used 
for analysis of safety and laboratory data. The Full Analysis Set (FAS) will include 
all subjects in the SAF who have baseline and at least one post-baseline value of 
GA area size via FAF in the study eye. The FAS will be used for analysis of efficacy 
data.  
Data Descriptions 
Data will be summarised by the subject population (SS, FAS, and subsets as 
applicable), Cohort/dose group (Cohorts 1 to 7, dose group 
 vg, and 
overall subjects), eye (Treated [Study Eye]/Untreated [Fellow Eye] for ocular 
evaluations and tests), and assessment (Weeks 1 to 48, or early termination, where 
appropriate). The long-term follow-up data (Visits 9 to 13) will be reported 
separately. 
Categorical variables will be summarised as the number and percentage of subjects, 
and frequencies of events (if appropriate). Continuous variables will be summarised 
as number of subjects, mean, median, standard deviation, minimum, and maximum 
statistics. Graphical displays appropriate to these types of data may be used to 
present any important findings. 
Demographics and Baseline Characteristics 
Medical history and measures at baseline including: demographics, medical/surgical 
history, concomitant medication, laboratory safety, urine pregnancy testing will be 
summarised descriptively by dose and route of administration. No formal 
comparisons of the Cohorts will be made. Assessments made at screening/baseline 

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and post-surgery will only be included in their respective safety and efficacy tables, 
together with any post-baseline assessments. 
Efficacy Assessments 
Efficacy assessments to evaluate the anatomical and functional visual outcomes 
involve: GA area size (via FAF), 
 
, 
, 
 
 For 
continuous variables, the change from baseline will be derived and presented 
together with actual values over time (visit) by dose and route of administration, and 
by eye (Treated [Study Eye]/Untreated [Fellow Eye]). Categorical variables from any 
ocular evaluations will be presented by classification over time (visit) by dose and 
route of administration, and by eye (Treated [Study Eye]/Untreated [Fellow Eye]).  
  
 
 
 
 
Safety Assessments 
Safety evaluations are considered to be of key importance for this study and include: 
AEs, ophthalmic examinations, BCVA (ETDRS) score, vital signs, laboratory safety 
(biochemistry and haematology), and 
 
 
Adverse events will be summarised in two parts: systemic events and ocular events. 
For systemic events, data will be summarised by dose and route of administration. 
Ocular events will be summarised by dose and route of administration and by eye 
(Treated [Study Eye]/Untreated [Fellow Eye]). 
All AEs (Overall, by seriousness, by severity, by relationship to GT005 or the 
procedure) recorded throughout the investigation will be reported following 
classification according to the Medical Dictionary for Regulatory Activities dictionary 
(for system organ class and preferred term).  
Systemic safety evaluations including vital signs, laboratory safety 
 
 will be summarised over time by dose and route of administration. 
Ocular safety evaluations including ophthalmic examination variables (cataract 
grading, intra-ocular pressure, etc.) and BCVA scores, will be summarised in the 
same manner as ocular efficacy variables, dependent on data type. 
Power and Sample Size 
As this is a first in human exploratory Phase I/II study, no formal sample size has 
been calculated. 
MONITORING COMMITTEES 
Data Safety Monitoring Board (DSMB) 
Composition 
A DSMB will be formed to review all safety data at predetermined intervals during 
the study. Additional DSMB meetings may be held as needed or at the request of 
the DSMB members. The DSMB is an independent committee that includes at 
least three individuals who cumulatively have the clinical and medical expertise to 
monitor the safety of subjects in the clinical study and will include a minimum of 

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one clinician expert in the management of AMD and clinical immunology. The 
DSMB will be chaired by one of the clinical experts who will attend all meetings. 
No DSMB member will be an Investigator in this study. 
 
Roles and Responsibilities of DSMB 
The roles and responsibilities of the DSMB are defined in the DSMB Charter, which 
include, but are not limited to: 
• 
Monitoring and reviewing all safety issues relative to the conduct of the 
study 
• 
Ensuring the protection and safety of subjects participating in the study 
• 
Recommending dose escalation in accordance with available safety data 
and study stopping rules 
• 
Recommending a different BCVA threshold for entry into the study, as 
appropriate  
• 
Providing recommendations to continue, modify the design, suspend or 
terminate the study depending upon emerging safety data 
• 
Communicating other recommendations or concerns as appropriate 
Dose Escalation 
• 
The DSMB will meet after the third subject has been enrolled (recruitment 
and treatment will continue at the current dose – there will be no study 
hold) in Cohorts 1 to 3, and in Cohort 5 
• 
If treatment has been tolerated and stopping rules have not been met, 
the DSMB will recommend to Gyroscope that enrolment of the next 
study Cohort can commence 
• 
Screening of potential subjects will be allowed prior to the DSMB 
meeting and decision, but treatment must not be administered to 
subjects in the higher dose group until the outcome of the DSMB 
recommendation has been provided in writing to Gyroscope  
Details regarding the DSMB mission and content of the DSMB data safety reviews 
will be specified in the DSMB charter. 
 

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SCHEDULE OF ASSESSMENTS 
Table 1: Clinical Schedule (Screening to Week 48) 
 
Local Site1 
Surgical Site 
Surgical or Local Site 
Local Trial Site1 
Early 
Termination 
Visit 
Assessment 
Visit 1 
Screening2 
 
Day -56 
to -1 
(-8 weeks) 
Visit 2 Dosing 
 
Tel call 
 
Visit 34 
 
Week 1 
+3 days 
 
Tel call 
 
Week 2 
+3 
days 
Visit 4 
 
Week 5 
-7/+3 
days 
Visit 4.1 
 
Week 8 
±7 days 
Visit 5 
 
Week 12 
±7 days 
Visit 6 
 
Week 24 
±7 days 
Visit 7 
 
Week 36 
±7 days 
Visit 8 
 
Week 48 
±7 days 
 
Pre-
surgery 
Day 13 
Surgery 
Day 1 
Post-
surgery 
Day 2 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
Review of Inc/Exc criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test6 
X 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Biochemistry/Haematology 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum sample for CFI 
levels8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for sequencing of 
complement genes8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery and dosing (GT005) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Discharge from unit 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events – 
AE/TEAE/TESAE15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Local Site1 
Surgical Site 
Surgical or Local Site 
Local Trial Site1 
Early 
Termination 
Visit 
Assessment 
Visit 1 
Screening2 
 
Day -56 
to -1 
(-8 weeks) 
Visit 2 Dosing 
 
Tel call 
 
Visit 34 
 
Week 1 
+3 days 
 
Tel call 
 
Week 2 
+3 
days 
Visit 4 
 
Week 5 
-7/+3 
days 
Visit 4.1 
 
Week 8 
±7 days 
Visit 5 
 
Week 12 
±7 days 
Visit 6 
 
Week 24 
±7 days 
Visit 7 
 
Week 36 
±7 days 
Visit 8 
 
Week 48 
±7 days 
 
Pre-
surgery 
Day 13 
Surgery 
Day 1 
Post-
surgery 
Day 2 
Abbreviations: AAV2=adeno-associated virus vector serotype 2; AE=adverse event; BCVA=best corrected visual acuity; CFI=complement factor I; FAF=fundus autofluorescence; 
ICF=informed consent form; Inc/Exc=inclusion/exclusion; LLVA=low luminance visual acuity; TEAE=treatment-emergent adverse events; Tel=telephone; TESAE=Treatment-emergent serious 
adverse events. 
1. 
Dependent upon location and Sponsor approvals, a Surgical Site may also act as a Local Site. 
2. 
Screening assessments may be conducted over several days. The 8-week screening period may be extended up to 12 weeks if agreed by the Sponsor Medical Monitor. If the screening 
period is extended past the original 8 week screening period (8-12 weeks), standard ophthalmic exam, haematology/biochemistry, and visual acuity (BCVA/LLVA) assessments should be 
repeated. In the event the GT005 administration is deferred during the surgical procedure (e.g., due to an AE occurring during surgery) the screening period may be extended up to 16 
weeks if agreed by the Sponsor Medical Monitor. Additionally, if the screening period is extended past 12 weeks (12–16 weeks), in case of GT005 deferral, standard ophthalmic exam, 
haematology/biochemistry, visual acuity (BCVA/LLVA), and FAFs will be repeated. 
3. 
Pre-surgery assessments will include any local requirements of the surgical site. Pre-surgery assessments should be performed within 7 days prior to surgery. 
4. 
Visit 3 will take place at the assigned surgical site, however this may be held at the local site if more practical.  
5. 
Subjects will be consented using a separate ICF for the additional four years of long-term follow-up at this visit. 
6. 
Only for women of childbearing potential. 
7. 
Urine pregnancy test (for women of childbearing potential) if the one performed at screening is more than 14 days old. 
8. 
Not required at Screening if already available through participation in a previous Gyroscope sponsored study. 
 
 
 
 
 
 
 
14. 12 to 24 hours post dosing, prior to discharge. 
15. All AEs should be captured from signing the informed consent form. Additional imaging or functional assessments may be conducted, as needed, to allow for safety assessment. 
 

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Table 2: Schedule of Visual Tests (Screening to Week 48) 
Assessment 
Local 
Site1 
Surgical Site 
Surgical or Local Site 
Local Trial Site1 
Early 
Termination 
Visit 
Visit 1 
Screening2 
 
Day -56 
to -1 
(-8 weeks) 
Visit 2 
Dosing 
Tel 
call 
Visit 34 
 
Week 1 
+3 days 
Tel Call 
 
Week 2 
+3 days 
Visit 4 
 
Week 5 
-7/+3 days 
Visit 4.1 
 
Week 8 
±7 days 
Visit 5 
 
Week 12 
±7 days 
Visit 6 
 
Weeks 24 
±7 days 
Visit 7 
 
Week 36 
±7 days 
Visit 8 
 
Week 48 
±7 days 
 
Pre-surgery 
Day 13 
Surgery 
Day 1 
Post-surgery 
Day 2 
 
 
 
 
 
 
 
 
 
 
Standard 
ophthalmic 
examination 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pre-surgery 
ocular safety 
check 
 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Colour fundus 
photography  
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Fundus 
autofluorescence  
X 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
OCT macula 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
OCT-A7 
X 
 
 
 
 
X8 
X8 
Fluorescein 
angiography7 
X 
 
 
 
 
X8 
X8 
Microperimetry9 
X 
X10 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
Additional 
functional 
assessments (if 
required)11 
 
 
 
 
 
 
 
X11 
X11 
Visual Acuity: 
BCVA and LLVA 
using ETDRS 
X 
 
 
 
 
X12 
 
X12 
X12 
X 
X 
X 
X 
X 
Visual acuity 
check 
 
X13 
 
 
 
 
 
 
 
 
 
 
 
 

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Submission of 
historical FAFs 
and/or OCTs15 
X 
Abbreviations: BCVA=best corrected visual acuity; CNV=choroidal neovascularisation; ETDRS=early treatment diabetic retinopathy study chart; FA=fluorescein angiography; LLVA=low 
luminance visual acuity; MAIA=macular integrity assessment; MNRead=Minnesota low vision reading; OCT=optical coherence tomography; OCT-A=optical coherence tomography 
angiography; Tel=telephone; 
. 
1. 
Dependent upon location and Sponsor approvals, a Surgical Site may also act as a Local Site 
2. 
Screening assessments may be conducted over several days. The screening period may be extended up to a maximum of 12 weeks, if agreed by the Sponsor Medical Monitor. If the 
screening period is extended past the original 8-week screening period (8-12 weeks), standard ophthalmic exam, haematology/biochemistry, and visual acuity (BCVA/LLVA) 
assessments should be repeated. In the event the GT005 administration is deferred during the surgical procedure (e.g., due to an AE occurring during surgery) the screening period may 
be extended up to 16 weeks if agreed by the Sponsor Medical Monitor. Additionally, if the screening period is extended past 12 weeks (12–16 weeks), in case of GT005 deferral, 
standard ophthalmic exam, haematology/biochemistry, visual acuity (BCVA/LLVA), and FAFs will be repeated. 
3. 
Pre-surgery assessments should be performed within 7 days prior to surgery. 
4. 
Visit 3 will take place at the surgical site, however this may be held at the local site if more practical. 
5. 
A pre-surgery ocular safety check will be performed to verify no new adverse events that could halt surgery.  
 
 
7. 
Other imaging modalities may be performed to assess for CNV if OCT-A is not available. In the event that the OCT/OCT-A images are inconclusive to rule out the presence of CNV the 
subject will be required to undergo an additional assessment via FA. At the Investigator’s discretion, FA may also be performed initially prior to the OCT/OCT-A results being available, 
but this is not mandatory. 
8. 
OCT-A and/or fluorescein angiography may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD. 
9. 
Microperimetry should be performed during scheduled visits at sites with a MAIA microperimeter: Microperimetry will be performed at either screening or prior to surgery (within the 
screening visit window) and may be performed over >1 day if needed. If in the view of the Investigator, the subject is not capable of performing the test, this will not be considered an 
exclusion to study participation. Microperimetry assessment instructions will be provided in the imaging manual.  
10. If omitted at screening, assessments should be performed during the pre-surgery visit. 
 
 
 
12. LLVA is not performed at Visits 3, 4 and 4.1. 
13. A visual acuity check using ETDRS or Snellen chart (near card is permissible) must be performed on the study eye if >4 weeks have lapsed since the last BCVA with ETDRS 
assessment. If Snellen result is >3 lines (BCVA equivalent to 15 letters) worse than the previous BCVA ETDRS score, then a BCVA with ETDRS assessment must be repeated. If the 
BCVA ETDRS score in the study eye is either >15 letters worse than the previous BCVA ETDRS score or <24 letters score (Cohorts 4 to 7), the surgery must be postponed pending 
discussion and approval by the Sponsor Medical Monitor. 
 
15. Enrolled subjects will be asked if they are willing to consent to have historical FAF and/or OCT images that were obtained within 1 year prior to enrolment, if available, provided to the 
sponsor. 
 
 
 

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Table 3: Follow-up Schedule (Week 72 to Week 240) 
Assessment 
Local Trial Site1 
Unscheduled 
Visit/ Early 
Termination2 
Visit 9 
 
Week 72 (Year 1.5) 
±30 days 
Visit 10 
 
Week 96 (Year 2) 
±30 days 
Visit 11 
 
Week 144 (Year 3) 
±30 days 
Visit 12 
 
Week 192 (Year 4) 
±30 days  
Visit 13 
 
Week 240 (Year 5) 
±30 days  
Standard ophthalmic examination 
X 
X 
X 
X 
X 
X 
Colour fundus photography 
X 
X 
X 
X 
X 
X 
Fundus autofluorescence  
X 
X 
X 
X 
X 
X 
OCT macula 
X 
X 
X 
X 
X 
X 
OCT-A3 
X4 
X4 
Fluorescein angiography3 
X4 
X4 
Visual acuity: BCVA/LLVA using ETDRS 
X 
X 
X 
X 
X 
X 
Microperimetry 
X 
X 
X 
X 
X 
X 
Additional functional assessments (if 
required)6 
X 
X 
X 
X 
X 
X 
AE/SAE monitoring7 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
Submission of historical FAFs and/or 
OCTs9 
X 
Abbreviations: AAV2=adeno-associated virus vector serotype 2; AE=adverse event; BCVA=best corrected visual acuity; CFI=complement factor I; CNV=choroidal 
neovascularisation; ETDRS=early treatment diabetic retinopathy study chart; FA=fluorescein angiography; LLVA=low luminance visual acuity; MNRead=Minnesota low 
vision reading; OCT=optical coherence tomography; OCT-A=optical coherence tomography angiography; SAE=serious adverse event; 
 
. 
1. 
Dependent upon location and Sponsor approvals, a Surgical Site may also act as a Local Site 
2. 
Minimum study assessments shown; additional assessments may be performed if clinically indicated. 
 
 
3. 
Other imaging modalities may be performed to assess for CNV if OCT-A is not available. In the event that the OCT/OCT-A images are inconclusive to rule out the 
presence of CNV the subject will be required to undergo an additional assessment via FA. At the Investigator’s discretion, FA may also be performed initially prior to the 
OCT/OCT-A results being available, but this is not mandatory. 
4. 
OCT-A and/or fluorescein angiography may be performed during the study period if clinically indicated, for example, if a subject converts to wet AMD.  

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Assessment 
Local Trial Site1 
Unscheduled 
Visit/ Early 
Termination2 
Visit 9 
 
Week 72 (Year 1.5) 
±30 days 
Visit 10 
 
Week 96 (Year 2) 
±30 days 
Visit 11 
 
Week 144 (Year 3) 
±30 days 
Visit 12 
 
Week 192 (Year 4) 
±30 days  
Visit 13 
 
Week 240 (Year 5) 
±30 days  
 
 
 
 
 
7. Additional tests/assessments (i.e., blood tests, imaging or functional assessments) may be conducted, as needed, to allow for safety monitoring. 
 
 
   
9. 
Enrolled subjects will be asked if they are willing to consent to have historical FAF and/or OCT images that were obtained within 1 year prior to enrolment, if available, 
provided to the sponsor. 

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CONTACT NAMES AND ADDRESSES 
Sponsor: 
Gyroscope Therapeutics Limited 
Address: 
Rolling Stock Yard, 
188 York Way, 
London, 
N7 9AS 
United Kingdom 

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ABBREVIATIONS 
AAV 
Adeno-associated virus 
AAV2 
Adeno-associated virus vector serotype 2 
ADA 
Anti-drug antibodies 
AE(s) 
Adverse event(s) 
AESI 
Adverse events of special interest 
AMD 
Age-related macular degeneration 
AREDS 
Age-related Eye Disease Study 
ATA 
Anti-transgene antibodies 
BCVA 
Best corrected visual acuity 
BSS 
Balanced Salt Solution 
C3 
Complement Component 3 
CFI/CFI 
Complement Factor I (Gene/PROTEIN) 
CFP 
Colour fundus photography 
CMO 
Cystoid macular oedema 
CNV 
Choroidal neovascularisation 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organisation 
CS 
Complement system 
CSR 
Clinical study report 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
FAF 
Fundus autofluorescence 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First in Human 
GA 
Geographic atrophy (also known as macular atrophy) 
GCP 
Good Clinical Practice 
hCFI 
Human Complement Factor I 
HEK-293 
Human embryonic kidney-293 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IRB(s) 
Institutional Review Board(s) 
IOP 
Intraocular pressure 
LLVA 
Low luminance visual acuity 
MAIA 
Macular integrity assessment 

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MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
 
 
MP 
Microperimeter 
N/A 
Not applicable 
 
 
OCT 
Optical coherence tomography 
OCT-A 
Optical coherence tomography angiography 
PSC 
Posterior subcapsular 
PRL 
Preferred retinal locus 
PSA 
Prostate-specific antigen 
REC 
Research Ethics Committee 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SD-OCT 
Spectral domain optical coherence tomography 
SDS 
Subretinal Delivery System 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event  
UK 
United Kingdom 
US 
United States 
 
 
Vg 
Vector genomes 

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TABLE OF CONTENTS 
PROTOCOL SIGNATURES ......................................................................................... 2 
AMENDMENT HISTORY .............................................................................................. 3 
PROTOCOL SYNOPSIS............................................................................................. 21 
STUDY DESIGN .......................................................................................................... 30 
SCHEDULE OF ASSESSMENTS .............................................................................. 31 
CONTACT NAMES AND ADDRESSES .................................................................... 37 
ABBREVIATIONS ....................................................................................................... 38 
TABLE OF CONTENTS .............................................................................................. 40 
LIST OF TABLES ....................................................................................................... 43 
LIST OF FIGURES ...................................................................................................... 43 
1. BACKGROUND INFORMATION AND STUDY RATIONALE ........................... 44 
1.1. 
Age-related Macular Degeneration ............................................................ 44 
1.2. 
Gene Therapy Medicinal Product .............................................................. 44 
1.3. 
Preclinical Data ............................................................................................ 45 
1.4. 
Clinical Data .................................................................................................. 47 
1.5. 
Orbit Subretinal Delivery System Medical Device ................................... 47 
1.6. 
Risks/Benefits .............................................................................................. 47 
1.6.1. 
Potential Risks ......................................................................................... 47 
1.6.2. 
Potential Benefits .................................................................................... 51 
1.6.3. 
Risk Benefit Analysis ............................................................................... 52 
1.7. 
Dose Rationale ............................................................................................. 52 
1.8. 
Trial Conduct ................................................................................................ 54 
1.9. 
Population ..................................................................................................... 54 
2. STUDY OBJECTIVES .......................................................................................... 55 
3. STUDY DESIGN ................................................................................................... 57 
3.1. 
Overall Study Design and Plan Description ............................................. 57 
4. SUBJECT SELECTION CRITERIA ..................................................................... 60 
4.1. 
Subject Recruitment .................................................................................... 60 
4.2. 
Inclusion Criteria .......................................................................................... 60 
4.3. 
Exclusion Criteria ........................................................................................ 60 
4.4. 
Subject Withdrawals .................................................................................... 61 
4.4.1. 
Replacements ......................................................................................... 62 
5. CONCOMITANT MEDICATIONS ........................................................................ 63 
5.1. 
Permitted Concomitant Medications ......................................................... 63 
5.2. 
Non-permitted Concomitant Medications ................................................. 63 
6. TREATMENT(S) ................................................................................................... 64 
6.1. 
Appearance and Content ............................................................................ 64 
6.2. 
Dosage and administration ........................................................................ 64 
6.2.1. 
Dosage .................................................................................................... 64 
6.2.2. 
Administration .......................................................................................... 64 
6.3. 
Packaging ..................................................................................................... 64 
6.3.1. 
GT005 ...................................................................................................... 64 
6.3.2. 
Orbit Subretinal Delivery System (US only) ........................................... 65 
6.4. 
Labelling ........................................................................................................ 65 

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6.4.1. 
GT005 ...................................................................................................... 65 
6.4.2. 
Orbit Subretinal Delivery System (US only) ........................................... 65 
6.5. 
Investigational Medicinal Product Supply Chain ..................................... 65 
6.6. 
Blinding and Randomisation ...................................................................... 65 
6.7. 
Treatment Compliance ................................................................................ 65 
6.8. 
Drug Storage ................................................................................................ 65 
6.9. 
Drug and Surgical Device Accountability ................................................. 66 
7. STUDY PLAN ....................................................................................................... 67 
7.1. 
Visit 1 Screening (Day -56 to -1 [-8 weeks]); at Local Site (may be 
conducted over several days): ............................................................................. 67 
7.2. 
Visit 2 Day 2 (Post-Operative discharge); at a Surgical Site: ................. 70 
7.3. 
Telephone Call; from a Surgical Site: ....................................................... 70 
7.4. 
Visit 3 (Week 1 ± 3 days); at a Surgical Site: ............................................ 71 
7.5. 
Telephone Call (Week 2 ± 3 days); from a Surgical Site: ........................ 71 
7.6. 
Visit 4 (Week 5 -7/+3 days); at Local or Surgical Site: ............................ 71 
7.7. 
Visit 4.1 (Week 8 ± 7 days); at Local Site or Surgical site: ..................... 72 
7.8. 
Visit 5 (Week 12 ± 7 days); at Local Site or Surgical site: ...................... 72 
7.9. 
Visit 6 (Week 24 ± 7 days); at Local Site: .................................................. 73 
7.10. Visit 7 (Week 36 ± 7 days); at Local Site: .................................................. 74 
7.11. Visit 8 (Week 48 ± 7 days); at Local Site: .................................................. 75 
7.12. Visit 9 (Week 72 ± 30 days); at Local Site: ................................................ 75 
7.13. Visit 10 (Week 96 ± 30 days); at Local Site: .............................................. 76 
7.14. Visit 11 (Week 144 ± 30 days); at Local Site: ............................................ 77 
7.15. Visit 12 (Week 192 ± 30 days); at Local Site: ............................................ 77 
7.16. Visit 13 (Week 240 ± 30 days); at Local Site: ............................................ 78 
7.17. Unscheduled Visits ...................................................................................... 79 
7.17.1. 
Prior to Week 48 Visit .......................................................................... 79 
7.17.2. 
Post Week 48 to Week 240 Visit ......................................................... 79 
7.18. Early Termination Visit ................................................................................ 79 
7.18.1. 
Prior to Week 48 Visit: ......................................................................... 80 
7.18.2. 
Post Week 48 to Week 240 Visit ......................................................... 81 
8. STUDY PROCEDURES/EVALUATIONS............................................................ 82 
8.1. 
Clinical evaluations ..................................................................................... 82 
8.1.1. 
Demographics ......................................................................................... 82 
8.1.2. 
Medical History & Concomitant Medication Review ............................... 82 
8.1.3. 
Vital Signs ................................................................................................ 82 
8.1.4. 
Pregnancy Test ....................................................................................... 82 
8.2. 
Laboratory Evaluations ............................................................................... 82 
8.2.1. 
Clinical Laboratory Evaluations .............................................................. 82 
8.2.2. 
Non-standard Assays .............................................................................. 84 
8.2.3. 
Ophthalmic Procedures .......................................................................... 84 
8.2.4. 
Historical FAF and OCT images ............................................................. 87 
8.3. 
Contraceptive Requirements...................................................................... 88 
9. ADVERSE EVENT REPORTING ........................................................................ 90 

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9.1. 
Definitions ..................................................................................................... 90 
9.2. 
Expectedness ............................................................................................... 91 
9.3. 
Intensity of Adverse Event ......................................................................... 91 
9.4. 
Causality Assessment ................................................................................. 92 
9.5. 
Action Taken Regarding the Study Drug .................................................. 92 
9.6. 
Outcome ........................................................................................................ 92 
9.7. 
Recording Adverse Events ......................................................................... 93 
9.8. 
Reporting Serious Adverse Events and Adverse Events of Special 
Interest to the Sponsor .......................................................................................... 93 
9.9. 
Device Malfunctions .................................................................................... 94 
9.9.1. 
Definitions ................................................................................................ 94 
9.9.2. 
Recording Device Malfunction ................................................................ 94 
10. DATA MANAGEMENT ........................................................................................ 96 
10.1. Trial Documentation and Trial Confidentiality ......................................... 96 
10.1.1. 
Trial Documentation, eCRFs and Document Keeping........................ 96 
10.1.2. 
Confidentiality of Trial Documents and Subject Records ................... 97 
11. STATISTICAL ANALYSIS PLAN ........................................................................ 98 
11.1. Sample Size .................................................................................................. 98 
11.2. Population for Analysis ............................................................................... 98 
11.3. Statistical Analysis ...................................................................................... 98 
11.3.1. 
Demographics and Baseline Characteristics: ..................................... 99 
11.3.2. 
Efficacy ................................................................................................. 99 
 100 
11.3.4. 
Safety ................................................................................................. 100 
12. INSTITUTIONAL REVIEW BOARD (IRB)/ RESEARCH ETHICS COMMITTEE 
(REC) ......................................................................................................................... 101 
13. REGULATORY REQUIREMENTS .................................................................... 102 
14. PROTOCOL AMENDMENTS ............................................................................ 103 
14.1. Protocol Amendments and Protocol Deviations ................................... 103 
14.2. Protocol Deviations and Exceptions ....................................................... 103 
15. INFORMED CONSENT ...................................................................................... 104 
16. DIRECT ACCESS TO SOURCE DOCUMENTATION/DATA .......................... 105 
17. STUDY MONITORING ....................................................................................... 106 
18. QUALITY ASSURANCE .................................................................................... 107 
19. INSURANCE ....................................................................................................... 108 
20. CONFIDENTIALITY ........................................................................................... 109 
21. PREMATURE TERMINATION OF THE STUDY .............................................. 110 
22. RECORD RETENTION ...................................................................................... 111 
23. PUBLICATION OF RESULTS ........................................................................... 112 
24. STUDY COMMITTEES ...................................................................................... 113 
24.1. DATA SAFETY MONITORING BOARD .................................................... 113 
25. REFERENCES ................................................................................................... 115 
26. APPENDICES ..................................................................................................... 117 
26.1. Early Treatment Diabetic Retinopathy Study Scale - Example ............ 117 
. 
 
 

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26.3. AREDS Clinical Lens Grading System .................................................... 120 
26.4. Declaration of Helsinki .............................................................................. 124 
. 
 127 
26.6. Vitreous Haze Grading Scale.................................................................... 144 
 
LIST OF TABLES 
Table 1: Clinical Schedule (Screening to Week 48) .............................................. 31 
Table 2: Schedule of Visual Tests (Screening to Week 48) ................................. 33 
Table 3: Follow-up Schedule (Week 72 to Week 240) ........................................... 35 
 
53 
Table 5: Laboratory Parameters .............................................................................. 83 
 
 
LIST OF FIGURES 
Figure 1: Overview of the Study Design (Part 3 and 4 are US only) ................... 30 
 
 

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1. BACKGROUND INFORMATION AND STUDY RATIONALE 
1.1. Age-related Macular Degeneration 
Age-related macular degeneration (AMD) is the most common cause of blindness 
among the elderly in the industrialised world Jonasson 2014, affecting approximately 
36 to 40 million people globally Access Economics Report 2010. AMD is a 
progressive disease resulting in a blurred area or blank spot in the centre of vision 
NIH.  
AMD is classified into early, intermediate, and late stages Ferris 2013. Late stage 
AMD includes two morphological sub-types: neovascular AMD and geographic 
atrophy (GA, also known as macular atrophy) Chakravarthy 2010. For the purposes 
of this protocol, atrophic AMD will be used to reference the late stage population of 
patients that are classified with GA or advanced dry AMD. There are no approved 
therapies for atrophic AMD. 
Evidence has emerged which implicates chronic local inflammation and activation of 
the complement cascade in AMD pathogenesis Anderson 2010. A number of 
complement proteins have been identified as constituents of drusen, the hallmark 
extracellular deposits associated with AMD Anderson 2010. Four rare genetic 
variants of complement factors, involved in the alternative pathway (Complement 
Factor H, Complement Factor I CFI, Complement Factor B, and Complement 
component 3 C3) have been found in AMD patients Fritsche 2016. These results 
suggest that mutations in these genes strongly correlate with the likelihood of 
developing AMD Fritsche 2016. Another study confirmed these findings and, in 
addition, showed that low serum CFI levels associated with the presence of rare CFI 
variants are associated with a much higher risk of development of AMD Kavanagh 
2015. As CFI serves as a global down-regulator of the alternative pathway Lachmann 
2016, an increase in intra-ocular CFI level has the potential to dampen an 
over-activated complement system (CS) associated with AMD, reducing the 
progression of the disease. The subset of GA patients with CFI haploinsufficiency may 
respond better to treatment. Adeno-associated virus vector serotype 2 (AAV2) vector-
based CFI gene transfer (GT005) may have the potential to provide sustained 
expression of hCFI in AMD patients’ eyes. 
A more comprehensive review of AMD is provided in the Investigator’s Brochure (IB). 
1.2. Gene Therapy Medicinal Product 
GT005 is a delivery vector comprising a nucleotide sequence encoding CFI 
(rAAV2.CFI). 
 
 
 
 
 
 
 
GT005 is supplied as a single vial in an appropriately labelled carton as the secondary 
container and stored at ≤-60oC.  

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GT005 can be diluted with formulation buffer which consists of 
 
Further details regarding 
GT005 is provided in the IB and Pharmacy Manual. 
1.3. Preclinical Data 

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1.4. Clinical Data 
At the time of initiation of this clinical trial, no other clinical studies have been 
performed using GT005. GT005-01 is a first in human (FIH) study evaluating the 
subretinal injection to subjects presenting with GA due to AMD. 
1.5. Orbit Subretinal Delivery System Medical Device 
The Orbit Subretinal Delivery System (SDS) was developed to improve the safety 
profile of subretinal injections as compared with transvitreal procedure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Further details regarding the Orbit SDS are provided in the Orbit SDS Instructions for 
Use and the Orbit SDS Surgical Procedure Manual. 
1.6. Risks/Benefits 
A summary of data and guidance to the Investigator is provided in the IB. 
1.6.1. 
Potential Risks 
The risks associated with this study can be divided into those related to the GT005 
product, to the surgical delivery of GT005, and to the study assessments. 
1.6.1.1. 
Risks Associated with GT005 
There were no GT005-related systemic adverse effects with all doses tested in both 
the monkey and mouse toxicity studies.

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The potential risks associated with gene therapy are related to intraocular 
inflammation, immunogenicity, raised CFI levels, reproductive and developmental 
risks, and environmental risks as discussed below. 
Intraocular Inflammation was not identified as an unexpected or significant risk in 
the toxicology program
 
 
 
 
  
 
 
Immunogenicity evaluation of the recombinant AAV platform has been extensively 
used in over 200 clinical trials to date [Ginn 2018], several of which were ocular gene 
therapy studies using subretinal injection of AAV2 vector. There have been no 
reported ocular toxicities observed which have been attributed to an immune response 
to the capsid in the treated patients. When administered subretinally, the humoral and 
cellular immune response to the capsid has been limited compared to systemically 
administered recombinant AAVs. After repeat administration of voretigene 
neparvovec, there was little to no change reported in antibody titres to AAV capsid 
when measured in systemic circulation and seemingly no correlation between 
presence of anti-capsid antibodies and clinical safety or efficacy FDA 2017; Mingozzi 
2013. 
 
 
 
 
 
 
 
 
 
 
Raised CFI levels are expected locally in the retina without impacting the systemic 
CS. While inhibition of the CS has been associated with an increased risk of microbial 

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regresses over 24 hours when the subretinal fluid resolves and retinotomy self-seals. 
Structural recovery of the retina following iatrogenic detachment of the macula 
generally occurs within one month [Xue 2017]. 
 
 
 
 
 
 
 
 
 
Cataract formation is associated with any vitrectomy procedure. In a published study 
from Feng 2014, cataract appeared in approximately 40% of patients following pars 
plana vitrectomy and resulted in a cataract extraction over the following 2 years. In 
publicly available safety data, Voretigene Neparvovec, a subretinally delivered 
AAV2-RPE65 for the treatment of RPE65 retinal dystrophy, was administered in 
81 eyes and of those, 11 eyes (14%) from seven subjects had documented 
progression of existing cataract or formation of new cataract. Three subjects had their 
cataract successfully extracted and other cataract cases did not receive elective 
extraction procedures Voretigene Neparvovec FDA ACM 2017. The study population 
of advanced AMD subjects is expected to have a mean age above or equal to 60 years 
and therefore may have already undergone a cataract extraction. At screening, 
subjects participating in this GT005 study and assessed as likely to require cataract 
surgery during the 12-month study period will not be included, or will be offered the 
option of removing their cataract before being (re)screened in the study. Participants 
who develop cataracts during the study may undergo cataract surgery if deemed 
clinically necessary; if surgery is performed, it should be carried out at least 4 weeks 
before the Week 48 visit. 
Intraocular pressure elevation is a risk associated with vitrectomy procedures 
[Chang 2006] and periocular or topical steroids [Kersey 2006]. In publicly available 
safety data, Voretigene Neparvovec (Luxturna®), had reports of elevation in IOP in 8 of 
81 eyes treated (10%). Patients will have IOPs checked at every visit to ensure 
adequate monitoring and therapies prescribed as needed based on local standard. At 
screening, subjects with moderate or advanced glaucoma in the study eye will not be 
included in the study to minimise this risk.  
Worsening of vision is an uncommon risk associated with the surgical procedure or 
vitreous tap and could be the result of endophthalmitis or retinal damage. 
 
 
 
1.6.1.3. 
Suprachoroidal Cannulation Using Orbit Subretinal Delivery 
System (Cohorts 5 to 7) 
Previous generations of the Orbit SDS have been studied in one completed clinical 
study Heier 2019 and one on-going study Banin 2019.
 
 
 
 
 
  

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definitively lost in the atrophic area. The potential benefit would be to slow down GA 
extension and ultimately prevent future visual loss. 
1.6.3. 
Risk Benefit Analysis 
GT005 is in an early stage of clinical development therefore the potential risks are 
based on preclinical data and preliminary clinical data available scientific knowledge 
of AAV2 vectors carrying different transgenes for the treatment of various retinal 
conditions without significant AEs related to these Drug Products MacLaren 2014; 
Russell 
2017; 
Heier 
2017; 
Voretigene 
Neparvovec 
FDA 
ACM 
2017; 
FOCUS, NCT03846193]. The main product-related risks are the generation of cellular 
and/or humoral immune responses to the AAV capsid. Anti-transgene antibody 
immune responses seen in toxicology studies are considered to be species-specific 
and are therefore not expected in subjects with lifelong CFI exposure.  
The surgical techniques for the subretinal delivery of gene therapy build upon 
established subretinal procedures such as subretinal tissue plasminogen activator 
injection and has been further developed and successfully used for the Choroideremia 
gene therapy clinical studies MacLaren 2014; Xue 2017.  
 
 
 
 
 
 
 
 
 
  
Careful pre-dosing assessment and perioperative measures are planned to minimise 
and monitor any complication of GT005 treatment via either surgical procedure.  
The risk to subjects exposed to GT005 is therefore considered to be low and upon 
careful evaluation of the potential benefits afforded by such a treatment, the 
risk/benefit ratio of GT005 in the study population is favourable. 
1.7. Dose Rationale 

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1.8. Trial Conduct 
This study will be conducted in compliance with the protocol and according to Good 
Clinical Practice (GCP) and applicable regulatory standards. No deviation from the 
protocol will be implemented without the prior review and approval of the Research 
Ethics Committee (REC/Institutional Review Board [IRB]) and Competent Authority 
except where it may be necessary to eliminate an immediate hazard to a subject. In 
such a case, the deviation will be reported to the REC/IRB and Competent Authority 
as soon as possible. 
1.9. Population 
Subjects with bilateral GA due to AMD in the absence of neovascularisation will be 
enrolled into the study.  
As this is a FIH study, subjects with GA due to AMD and already some vision loss in 
the study eye have been chosen for Part 1 (Cohorts 1 to 3; dose-escalation). On 
completion of the dose escalation and review of the safety data by the Data Safety 
Monitoring Board (DSMB), subjects with better preserved vision, who potentially would 
be more likely to benefit from treatment, will be entered into Parts 2 (Cohort 4), 
3 (Cohorts 5 to 6), and 4 (Cohort 7) of the study. 
 

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2. STUDY OBJECTIVES 
The overall objectives of the study are to evaluate the safety, dose response and 
efficacy (anatomical and functional visual outcomes) of three doses of GT005 in 
subjects with GA due to AMD when delivered subretinally via the transvitreal 
procedure or suprachoroidal cannulation. 
 
Objectives 
Evaluation Criteria 
Primary 
• To evaluate the safety of GT005 
at 3 doses  
• Incidence of ocular and non-ocular 
treatment-emergent AEs (TEAEs) and 
treatment-emergent serious AEs 
(TESAEs) over 48 weeks 
Secondary 
• To evaluate long-term safety of 
GT005 at 3 doses 
• Incidence of ocular and non-ocular 
treatment-emergent AEs (TEAEs) and 
treatment-emergent serious AEs 
(TESAEs) up to 240 weeks 
• To evaluate the effect of GT005 
on anatomical and functional 
visual outcomes 
• Best corrected visual acuity (BCVA) 
and low luminance visual acuity (LLVA) 
score via the early treatment diabetic 
retinopathy study (ETDRS) chart up to 
240 weeks  
• Macular sensitivity as assessed by 
Mesopic Microperimetry up to 240 
weeks  
• Change in GA area size as assessed 
by fundus autofluorescence (FAF) up to 
240 weeks 
• To evaluate the performance of 
the Orbit SDS (US only) 
• Rate of successful delivery of balanced 
salt solution (BSS) or BSS PLUS to the 
subretinal space 
• Rate of successful delivery of GT005 to 
the subretinal space 
• To evaluate the safety of the 
Orbit SDS (US only) 
• Incidence of device-related AEs and 
SAEs 
 
• 
 
 
• 
 
 
 

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• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
 
 
• 
 
 
 
 

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3. STUDY DESIGN 
3.1. Overall Study Design and Plan Description 
This is an open label FIH Phase I/II multicentre study to evaluate the safety, dose 
response and efficacy of GT005 in subjects with GA due to AMD. The study will be 
conducted in four parts; Part 1 (Cohorts 1 to 3): dose-escalation, Part 2 (Cohort 4): 
dose-expansion, Part 3 (Cohorts 5 to 6): dose-escalation with the Orbit SDS, and 
Part 4 (Cohort 7): dose-expansion with the Orbit SDS.  
Parts 1 and 2 (Cohorts 1 to 4) will deliver GT005 via the standard transvitreal 
procedure and Parts 3 and 4 (Cohort 5 to 7) will deliver GT005 via the Orbit SDS. 
The Orbit SDS is a 510(k) cleared device in the US whereby Parts 3 and 4 (Cohorts 5 
to 7) will only be used at US sites. 
An overview of the study design is provided in Figure 1: Overview of the Study. 
Approximately 65 subjects will be enrolled: up to five in each of Cohorts 1 to 3, up to 
20 in Cohort 4, up to five in each of Cohorts 5 and 6, and up to 20 in Cohort 7. 
Part 1 (Cohorts 1 to 3; dose-escalation) will test three dose Cohorts (
 
 vg) of up to five subjects per Cohort. A minimum of three subjects per dose 
Cohort will be required to evaluate the safety of the respective dose. Sentinel dosing 
will be applied whereby there will be a minimum of 14 days separation between dosing 
of the first and second subject of each dose Cohort, to assess any acute reactions to 
surgery and short-term tolerability to GT005 prior to dosing the remaining subjects in 
each dose Cohort. Dose escalation will be evaluated by a DSMB and will be assessed 
based on the Week 5 data for the first three subjects dosed in Cohorts 1 and 2. The 
DSMB will review the Week 5 safety data for the first three subjects dosed in Cohort 3 
prior to dosing in further cohorts. The DSMB can be called upon by the Sponsor to 
perform safety evaluations as needed. 
Subjects will receive a single subretinal injection of GT005 at one of three dose levels:  
• Low dose: 
  
• Mid dose: 
 
• High dose: 
 
Part 2 (Cohort 4; dose-expansion) will enrol up to 20 subjects in Cohort 4 with GT005 
delivered via the transvitreal procedure to further characterise the safety, dose 
response and efficacy of GT005. On completion of dose escalation, dose levels 
determined to be safe and tolerable by the DSMB in Part 1 (Cohorts 1 to 3), may be 
assessed in Cohort 4. The exact number of subjects that will be enrolled in Cohort 4 
will be determined by the Sponsor based on the emerging safety, pharmacodynamic 
and clinical outcomes data.  
Part 3 (Cohort 5 to 6; dose-escalation and evaluation of two doses of GT005 delivered 
with the Orbit SDS; subretinal delivery via a suprachoroidal cannulation) will enrol 
three to five subjects at the mid dose (
 vg; Cohort 5) and three to five subjects at 
the high dose (
 vg; Cohort 6), to evaluate the safety of GT005 treatment when 
delivered via the Orbit SDS. Part 3 (Cohorts 5 to 6) is independent of, and may be 
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DSMB and will be assessed based on the Week 5 safety data for the first three 
subjects dosed in Cohort 5. 
Part 4 (Cohort 7; dose-expansion of GT005 delivered with the Orbit SDS; subretinal 
delivery via a suprachoroidal cannulation) will enrol up to 20 subjects in Cohort 7 to 
further characterise the safety, dose response, and efficacy of GT005 treatment when 
delivered via the Orbit SDS. On completion of dose-escalation, dose levels determined 
to be safe and tolerable by the DSMB in Part 1 (Cohorts 1 to 3) may be assessed in 
Cohort 7. The exact number of subjects that will be enrolled in Cohort 7 will be 
determined by the Sponsor based on the emerging safety, pharmacodynamic and 
clinical outcomes data. 
Analyses of data from the Orbit SDS will be based on data accumulated from US sites. 
The study treatment consists of an AAV2 expressing hCFI. The treatment is 
administered as a single subretinal injection into one eye – “the study eye”. Both eyes 
will be assessed at the screening visit. If both eyes meet the eligibility criteria the study 
eye will be the worse seeing eye or the eye with the largest GA size for eyes with 
equivalent visual acuity unless the subject (in consultation with the surgeon) expresses 
an alternative preference. 
The study will, for the individual subjects, consist of up to 13 visits over a 5-year period. 
All subjects will be assessed for the occurrence of AEs at each visit and will undergo 
functional visual and retinal imaging/anatomical assessments and biological sampling 
as per the schedule of assessments.  
Following consent, subjects will undergo a number of ophthalmic and clinical 
assessments to determine eligibility for inclusion in the study. Once eligibility is 
confirmed by the Sponsor, the subject will be enrolled. The subject will be scheduled 
for surgery 
 
 
Data from subjects screened in another Gyroscope sponsored study at the same 
Investigative site as FOCUS may be used to fulfil the screening and eligibility 
requirements for this study. This is only permissible if the screening data are collected 
within the screening period specified in the clinical protocol. Following consent, 
subjects will undergo ophthalmic and clinical assessments to determine eligibility for 
inclusion in the study. Should subjects fail to meet the eligibility for FOCUS, they will 
be classed as screen failures for this study and may be considered for entry into 
another Gyroscope sponsored study. 
At the screening visit, baseline assessments will be carried out including ophthalmic 
examination, measurements of the size of GA, retinal examination, microperimetry and 
visual acuity (BCVA and LLVA). OCT angiography (OCT-A; or other imaging modality 
if OCT-A is not available) and fluorescein angiography (FA) may be performed at 
screening to assess presence of occult CNV. In the event, that the OCT/OCT-A 
images are inconclusive to rule out the presence of CNV, the subject will be required 
to undergo an additional assessment via FA. At the Investigator’s discretion, FA may 
also be performed prior to the OCT/OCT-A results being available, but this is not 
mandatory. Blood samples will be taken for safety assessments, genotyping (if 
required), immunogenicity assessment as well as standard biochemistry and 
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4. SUBJECT SELECTION CRITERIA 
4.1. Subject Recruitment 
Subjects will be recruited from the population of outpatients at the study sites. 
Potentially eligible subjects interested in taking part in the study may be referred from 
other sites. 
The Investigator will keep records of all subjects screened and included. The reason 
for screen failure should be stated for all subjects screened but not included. Subjects 
who are eligible but do not receive treatment with GT005 will be classed as screen 
failures and may be replaced. The reason for withdrawal should be stated for all 
subjects included but not completed.  
4.2. Inclusion Criteria 
For inclusion in the study, subjects must fulfil all of the following criteria: 
1. Able and willing to give consent to study participation 
2. Have a clinical diagnosis of GA secondary to AMD in the study eye, as 
determined by the Investigator, and a diagnosis of AMD in the contralateral 
eye (except if the subject is monocular)  
3. Cohorts 1 to 6: GA lesion(s) total size in the study eye must be ≥1.25mm2 and 
≤17.5mm2  
Cohort 7: GA lesion(s) total size in the study eye must be ≥1.25mm2 
4. GA lesion(s) in the study eye must reside completely within the FAF fundus 
image 
5. Cohorts 1 to 3: BCVA of ≤50 letters (6/36 Snellen acuity equivalent or worse) 
using ETDRS charts in the study eye  
Cohorts 4 to 7: BCVA of ≥24 letters (6/95 and 20/320 Snellen acuity 
equivalent or better) using ETDRS charts in the study eye  
6. Aged ≥55 years 
7. Able to attend all study visits and complete the study procedures 
8. Women of child-bearing potential need to have a negative urine pregnancy 
test within two weeks prior to receiving the drug. A pregnancy test is not 
required for postmenopausal women (defined as being at least 12 
consecutive months without menses) or those surgically sterilised (those 
having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal 
occlusive procedure, hysterectomy, or bilateral oophorectomy)  
4.3. Exclusion Criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled: 
1. Have evidence or history of CNV in the study eye. Subjects are permitted to 
have CNV in the fellow eye defined as either: 
a. Non-exudative/sub-clinical fellow eye CNV identified at screening, or 

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b. Known history of fellow eye CNV with either ≥2 years since diagnosis or 
with no active treatment required in 6 months prior to screening 
2. Presence of moderate/severe non-proliferative, diabetic retinopathy or worse 
in the study eye 
3. Have history of vitrectomy, sub-macular surgery, or macular photocoagulation 
in the study eye 
4. History of intraocular surgery in the study eye within 12 weeks prior to 
Screening (Visit 1). 
 
 
5. Have clinically significant cataract that may require surgery during the study 
period in the study eye 
6. Presence of moderate to severe glaucomatous optic neuropathy in the study 
eye; uncontrolled IOP despite the use of more than two topical agents; a 
history of glaucoma-filtering or valve surgery is also excluded 
7. Axial myopia of greater than -8 diopters in the study eye 
8. Have received any investigational product for the treatment of GA within the 
past 6 months or 5 half-lives (whichever is longer), other than nutritional 
supplements such as the age-related eye disease study (AREDS) formula 
9. Have received a gene or cell therapy at any time 
10. Have a contraindication to the specified protocol corticosteroid regimen 
11. Are unwilling to use two forms of contraception (one of which being a barrier 
method) for 90 days post-dosing, if relevant 
12. Active malignancy within the past 12 months, except for: Appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate 
cancer with a stable prostate-specific antigen (PSA) ≥12 months 
13. Have any other significant ocular or non-ocular medical or psychiatric 
condition which, in the opinion of the Investigator, may either put the subject 
at risk or may influence the results of the study 
14. Cohorts 5 to 7 only: presence of metallic objects or implanted stimulator 
devices in or near the head, including cochlear implants, deep brain 
stimulators, vagus nerve stimulators, and other implanted electrodes or 
stimulators 
4.4. Subject Withdrawals 
In all circumstances, subjects will be made aware of their right to refuse participation 
in a clinical study and are entitled to freely withdraw their informed consent, without 
giving reasons. Subjects should be assured that withdrawal from the study will not 
cause prejudice, will not result in any determinant, and will not affect treatment. In 
addition, refusal to give consent or withdrawal of consent to participate in research 
must not lead to any liability or discrimination (e.g., with regard to insurance or 
employment) against the person concerned. 
It is important to note that it is impossible for the GT005 product to be removed from 
the subretinal space after injection. Therefore, once surgery has taken place, subjects 
can withdraw from the study but cannot withdraw from treatment. 

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The Investigator also has the right to withdraw subjects from the study (e.g., in the 
case of non-compliance with the protocol and/or lack of willingness or commitment to 
co-operate in all phases of the study, or in the case of an AE which is considered 
intolerable by the subject and/or legal representative). Long-term safety assessment 
of subjects treated with a gene therapy product is a regulatory requirement and every 
effort will be made to at least continue monitoring long-term subject safety. 
Should a subject decide to withdraw for any reasons, all efforts will be made to 
complete and report the observations as thoroughly as possible. A complete final 
evaluation at the time of withdrawal will be performed with an explanation of the exact 
reason why the subject is withdrawing from the study. 
The Investigator is responsible for the optimal individual treatment of the subject. 
The Investigator must fill in the “early termination visit” in the electronic case report 
form (eCRF) explaining all reasons for withdrawal.  
If the subject withdraws consent, the Sponsor may retain and continue to use any data 
collected before withdrawal of consent. 
The Investigator will provide or arrange for appropriate follow-up (if required) for 
subjects withdrawing from the study. After a subject withdraws from the study, the 
Investigator is still responsible for reporting SAEs considered causally related to the 
study drug. In addition, the Investigator needs to ensure appropriate treatment and 
follow-up of each AE still ongoing at the time of the subject’s discontinuation. 
All subjects participating in the clinical study will receive an alert card from the 
Investigator, which has been previously agreed by the Sponsor and approved by the 
Ethics Committee. At a minimum it will contain the name of the subject, the Investigator 
contact number and information regarding the medical treatment received by the 
subject. 
Whether a subject is withdrawn from the study at their own request or based on a 
decision of the Investigator, follow-up should be maintained, subject to the consent of 
the subject. 
4.4.1. 
Replacements 
Subjects who are eligible but do not receive treatment will be classed as screen 
failures and may be replaced. A subject can be screened twice if the reason for 
ineligibility is transient (e.g., a cataract requiring cataract extraction), to allow the 8-
week time interval between baseline assessment of the screening visit and dosing to 
be maintained. Furthermore, subjects with borderline screening assessments (e.g., 
laboratory parameters) can be re-tested once within the assigned screening period.  
In the event, that a subject withdraws from the study for any reason other than an AE 
or other safety concern or is lost to follow-up within 6 months (Week 24) post-dosing, 
the subject may be replaced. The reason for the subject’s withdrawal from the study 
must be recorded.  
 

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5. CONCOMITANT MEDICATIONS 
5.1. Permitted Concomitant Medications 
During the course of the study, subjects will be allowed to continue taking all 
prescribed and non-prescribed medications, unless excluded as per the study 
protocol. Note that AREDS based supplements are permitted as no effect on 
progression of GA has been reported. 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to administering the corticosteroid therapy, Investigators must refer to relevant 
Summary of Product Characteristics (SmPC) and/or label guidance for use.  
Concomitant medications will be checked throughout the study and any change in 
medication after the date on which the subject signs the informed consent should be 
recorded in the eCRF. 
5.2. Non-permitted Concomitant Medications 
There are no contraindicated medications for GT005 treatment. Potential subjects who 
previously received a gene/cell-based therapy at any time are excluded.  
 

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6. TREATMENT(S) 
6.1. Appearance and Content 
GT005 is supplied as a single vial containing 
 of AAV2 virus vector 
expressing hCFI. 
6.2. Dosage and administration 
6.2.1. 
Dosage 
GT005 will be administered at one of three dose levels: 
• Low dose: 
  
 
 
 
 
6.2.2. 
Administration 
The product is delivered by trained vitreoretinal surgeons as a single administration by 
subretinal injection under local anaesthesia. Other anaesthetic options will be 
considered by the surgeon as appropriate for the subject. The injection volume will be 
0.1mL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3. Packaging 
6.3.1. 
 GT005 
GT005 and diluent are both supplied in single vials in an appropriately labelled carton 
as the secondary container. GT005 and diluent will be stored at ≤-60oC. 

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6.3.2. 
Orbit Subretinal Delivery System (US only) 
 
 
 
 
 
 
Further details regarding the Orbit SDS are provided in the Instructions for Use and 
the Orbit SDS Surgical Procedure Manual. 
6.4. Labelling 
6.4.1. 
GT005 
All study medications will be labelled in accordance with Annex 13: Manufacture of 
investigational products and specific local requirements. 
6.4.2. 
 Orbit Subretinal Delivery System (US only) 
All study devices are labelled in accordance with FDA regulations for marketed 
products. The label contains key elements such as part number, lot number, and 
expiration date. A label stating, ‘For use in clinical trial GT005-01’ and site specific 
information is applied to the shipping container. 
6.5. Investigational Medicinal Product Supply Chain 
GT005 and diluent will be dispatched directly to sites from either UK or the US 
approved 3rd party distribution depots. 
6.6. Blinding and Randomisation 
This is an open label study. All participants will receive GT005.  
6.7. Treatment Compliance 
GT005 is delivered as a single administration by subretinal injection. The subretinal 
injection is undertaken by a qualified vitreoretinal surgeon at a surgical site. The 
Investigator at the surgical site is responsible for ensuring GT005 is handled in 
accordance with the protocol and is only administered to subjects enrolled into the 
study. Additionally, the Investigator at the surgical site is responsible for ensuring the 
Orbit SDS is handled in accordance with the relevant Surgical Manual and is only 
administered to subjects enrolled into the study. 
6.8. Drug Storage 
GT005 is supplied in a single vial in an appropriately labelled carton as the secondary 
container and stored at ≤ -60oC. 
Prior to administration, GT005 will be thawed at ambient temperature (15 to 25oC). 
Once thawed, GT005 should be held at ambient temperature and must be 
administered within the same business day of thaw and preparation. GT005 should be 
handled as per the Pharmacy Manual. 

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6.9. Drug and Surgical Device Accountability 
GT005 and all applicable surgical devices will only be delivered to the investigational 
site. 
All material supplied is for use only in this clinical study and should not be used for any 
other purpose. 
The Investigator or designee is responsible for GT005 accountability, reconciliation 
and record maintenance. The Investigator or designated site staff must maintain 
accountability records throughout the course of the study including records of the 
amount of GT005 received, the identification of the subject for whom it was dispensed 
and the date(s) and quantity of GT005 dispensed, and doses and volumes 
administered.  
These records must be available for inspection by a study monitor during the study.  
GT005 is a biosafety level 1 product. GT005 post-administration measures regarding 
destruction and disposal of GT005 and disposables are detailed in the Pharmacy 
Manual. 
The Investigator or designated staff member is responsible for maintaining inventory 
of the Orbit SDSs used. A record will be kept of the identification of Orbit SDSs, and 
the identification of the subject for whom the device was used. 
At the end of study enrolment, unused and unopened devices should be returned to 
the Sponsor and recorded in the accountability records. Accountability records must 
show the identification and quantity of devices returned and method of shipment (US 
only).  
 

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7. STUDY PLAN 
The timing and type of assessments required during the study are summarised in the 
Schedule of Assessments [Table 1: Clinical Schedule (Screening to Week 48); Table 
2: Schedule of Visual Tests (Screening to Week 48); Table 3: Follow-up Schedule 
(Week 72 to Week 240)]. 
Definition of Local Site versus Surgical Site 
Local investigational sites are defined as sites that are approved to participate in this 
clinical study but require identified subjects to be transferred for surgery. Subject 
consent, screening, and post-operative follow-up visits will be conducted according to 
the visit schedule outlined in the schedule of assessments.  
Surgical sites are defined as sites that are approved to participate in this clinical study 
and to perform the surgical procedure as part of this clinical protocol. 
Dependent upon location and Sponsor approvals, a surgical site may also act as a 
local site. In such cases, all study visits and assessments (as listed in Table 1, Table 
2, Table 3) for all timepoints, inclusive of Long-Term Follow-Up, will take place at the 
surgical site. 
7.1. 
Visit 1 Screening (Day -56 to -1 [-8 weeks]); at Local Site 
(may be conducted over several days): 
The Investigator will explain the study purpose, procedures, and subject 
responsibilities to each potential study subject. The subject’s willingness and ability to 
meet the protocol requirements will be determined. Prior to any study-specific 
procedure, written informed consent will be obtained. 
The subject will sign and date one copy of the consent form in the presence of the 
Investigator or his/her designee. The original signed form will be retained at the study 
site and an additional copy will remain in the subject’s medical records; a copy will 
also be given to the subject. 
 
 
 
 
  
Data from subjects screened in another Gyroscope sponsored study, conducted at the 
same Investigative site as the FOCUS study, may be used to fulfil the screening and 
eligibility requirements for this study. This is only permissible if the screening data are 
collected within the screening period specified in the clinical protocol. Should subjects 
fail to meet the eligibility for FOCUS, they will be classed as screen failures for this 
study and may be considered for entry into another Gyroscope sponsored study (see 
Section 4.4.1).  
After informed consent has been obtained, the subject will be evaluated to determine 
eligibility. Screening procedures will consist of the following:  
Inclusion/Exclusion (screen failures to be recorded), recording of demographics, 
medical/surgical history and concomitant medication. A urine pregnancy test (only for 

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women of childbearing potential), vital signs, and AEs will be completed prior to the 
following procedures:  
• Blood draws for: 
o Biochemistry and haematology 
o Serum CFI Levels (central laboratory, baseline measurement only) 
o 
 
o 
 
o Sequencing of complement genes. Note: this assessment is 
applicable to all subjects at the Screening Visit unless already 
completed in another Gyroscope sponsored study. 
o 
 
 
• Standard Ophthalmic Examination including indirect ophthalmoscopy, a 
slit-lamp examination, IOP measurement, assessment of anterior chamber and 
vitreous inflammation, and cataract grading 
• Colour fundus photography (CFP) 
• FAF 
• OCT macula 
• OCT-A; if the site does not have OCT-A other imaging modalities may be used 
to rule out CNV. In the event, that the OCT/OCT-A images are inconclusive to 
rule out the presence of CNV the subject will be required to undergo an 
additional assessment via FA 
• FA; if OCT/OCT-A images are inconclusive to rule out CNV. FA may also be 
performed initially prior to OCT/OCT-A results being available, but this is not 
mandatory 
• Microperimetry (assessment can be carried out over two days)  
Note: microperimetry is only applicable at sites with a macular integrity 
assessment (MAIA) microperimeter  
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
 
Eligibility assessment and confirmation 
Subject eligibility will be confirmed by the Sponsor on the basis of the following criteria: 
• GA lesions characteristics assessed by the central reader on the study eye 
• BCVA of the study eye 
• Investigator statement that the other eligibility criteria are met 
The vitreoretinal surgeon will also confirm the study eye. 

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Subjects whose eligibility is confirmed will be enrolled into the study, assigned a 
subject number and scheduled for surgery within 8 weeks of screening. The 8-week 
screening period may be extended up to a maximum of 12 weeks, if agreed by the 
Sponsor Medical Monitor.   
If the screening period is extended past the original 8-week screening period (8–12 
weeks), standard ophthalmic exam, haematology/biochemistry, and visual acuity 
(BCVA/LLVA) assessments should be repeated. In the event, that GT005 
administration is deferred during the surgical procedure (e.g., due to an AE occurring 
during surgery) the screening period may be extended up to 16 weeks if agreed by the 
Sponsor Medical Monitor. Additionally, if the screening period is extended past 
12 weeks (12–16 weeks), in case of GT005 deferral, standard ophthalmic exam, 
haematology/biochemistry, visual acuity (BCVA/LLVA), and FAFs will be repeated. 
Visit 2 will occur at a surgical site. Pre-surgery assessments will include any local 
requirements of the surgical site. Pre-surgery assessments should be performed 
within 7 days prior to surgery. The following assessment are also required pre-surgery: 
Timing 
Procedure 
Prior to Entering 
the Operating 
Room (within 
7 days prior to 
surgery) 
 
• Review of Medical/Surgical History including bleeding 
history  
• Vital signs 
• AE/SAE monitoring 
• Pre-surgery ocular safety check to verify there are no new 
ocular AEs that would halt surgery 
• Microperimetry, if this was omitted at screening, should be 
performed if feasible  
• Concomitant medication review including use of anti-
thrombotic drugs 
 
 
 
• Urine pregnancy test (for women of childbearing potential) 
if the one performed at screening is more than 14 days old 
• Blood draw for: 
 
 
• Visual acuity check:  
o A visual acuity check using ETDRS or Snellen chart 
(near card is permissible) must be performed on the 
study eye if >4 weeks have lapsed since the last BCVA 
with ETDRS assessment. If Snellen result is >3 lines 
(BCVA equivalent to 15 letters) worse than the previous 
BCVA ETDRS score, then a BCVA with ETDRS 
assessment must be repeated. If the BCVA ETDRS 
score in the study eye is either >15 letters worse than 
the previous BCVA ETDRS score or <24 letters score 
(Cohorts 4 to 7), the surgery must be postponed 

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Timing 
Procedure 
pending discussion and approval by the Sponsor 
Medical Monitor.  
Within the 
operating room 
 
 
 
  
 
 
 
 
 
• Dosing (subretinal injection of GT005) 
 
 
 
7.2. Visit 2 Day 2 (Post-Operative discharge); at a Surgical Site: 
Subjects will be maintained in the clinic for up to 24 hours following the subretinal 
injection to assess any acute issues resulting from the surgery. The following post 
dosing assessments will be performed: 
About 24 hours 
after dosing and 
prior to discharge 
• AE/SAE monitoring 
• Concomitant medication review 
• Standard ophthalmic examination  
• OCT macula 
 
 
• 
 
 
 
 
 
 
 
 
• Vital signs 
 
The subject will be reminded to use two forms of contraception (one of which being a 
barrier method) for 90 days for men and women of childbearing potential (see 
Section 8.3). 
7.3. Telephone Call; from a Surgical Site: 
Each participant must be contacted by telephone to assess 
 
 and AEs/SAEs within the following week post dosing. 

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7.4. Visit 3 (Week 1 ± 3 days); at a Surgical Site: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
• 
 
• Standard ophthalmic examination 
• OCT macula 
 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• BCVA using ETDRS 
 
 
7.5. Telephone Call (Week 2 ± 3 days); from a Surgical Site: 
Each participant must be contacted by telephone to 
 
 AEs/SAEs 14 days (Week 2) post dosing. 
7.6. Visit 4 (Week 5 -7/+3 days); at Local or Surgical Site: 
At Week 5, subjects may choose to attend a local site or surgical site for clinical 
assessments and ophthalmic imaging, with review of images by both the local site 
Investigator and the surgeon. 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
o 
 
• Standard ophthalmic examination 
• FAF 
• OCT macula 
 
 

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• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• BCVA using ETDRS 
 
 
 
 
 
7.7. Visit 4.1 (Week 8 ± 7 days); at Local Site or Surgical site: 
Recording of: concomitant medication, AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• Visual acuity (BCVA) using ETDRS 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
 
 
 
 
7.8. Visit 5 (Week 12 ± 7 days); at Local Site or Surgical site: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
• Standard ophthalmic examination 
• CFP 
• FAF 

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• OCT macula 
 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• Visual Acuity (BCVA and LLVA) using ETDRS 
• Microperimetry Note: microperimetry is only applicable at sites with a MAIA 
microperimeter 
 
 
 
 
 
 
 
 
 
 
7.9. Visit 6 (Week 24 ± 7 days); at Local Site: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• 
FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 

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• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
 
 
 
 
 
 
7.10. Visit 7 (Week 36 ± 7 days); at Local Site: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
 
 
 
 
 
 
 
 
 
• CFP 
• FAF 
• OCT macula 
 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• Visual Acuity (BCVA and LLVA) using ETDRS 
 
 

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7.11. Visit 8 (Week 48 ± 7 days); at Local Site: 
At this visit subjects will be invited to consent for additional follow-up for up to -5 years 
post-dosing. If a subject does not agree to consent to long-term follow-up as part of 
this study, any ongoing AEs will be followed until resolution with subject consent. 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
• 
 
7.12. Visit 9 (Week 72 ± 30 days); at Local Site: 
Recording of: concomitant medication and AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 

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• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
7.13. Visit 10 (Week 96 ± 30 days); at Local Site: 
Recording of: concomitant medication and AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
• 
• 
 

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• 
 
7.14. Visit 11 (Week 144 ± 30 days); at Local Site: 
Recording of: concomitant medication and AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual Acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
• 
 
 
 
 
 
• 
 
7.15. Visit 12 (Week 192 ± 30 days); at Local Site: 
Recording of: concomitant medication and AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 

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• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 
• 
 
 
 
 
 . 
• 
 
7.16. Visit 13 (Week 240 ± 30 days); at Local Site: 
Recording of: concomitant medication and AEs. 
The following procedures will be carried out: 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
• 
 

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• 
 
 
 
• 
 
7.17. Unscheduled Visits 
7.17.1. Prior to Week 48 Visit 
If clinically indicated, subjects may need to return to the site for an unscheduled visit. 
The Investigator will perform assessments considered to be appropriate for the 
participant, considering the reason behind the need to arrange an unscheduled visit. 
These results should be recorded in the subject’s medical notes and eCRF. 
7.17.2. Post Week 48 to Week 240 Visit 
If clinically indicated, subjects may need to return to the site for an unscheduled visit. 
The following assessments, along with any other assessments that are needed, may 
be completed at the discretion of the Investigator: 
• Recording of AEs and concomitant medication 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual Acuity (BCVA and LLVA) using ETDRS 
• 
 
  
• 
 
7.18. Early Termination Visit  
Subjects have the right to withdraw from the study at any time and for any reason. If a 
subject refuses to be seen for further visits, the assessments listed in the early 

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termination visit should be performed at the time they have indicated that they will not 
attend for further visits. 
Where a subject is withdrawn from the study at their own request or based on a 
decision of the Investigator, follow-up may be maintained, which may include 
telephone calls or follow-up visits arranged by the investigator, subject to the consent 
of the participant. 
 
7.18.1. Prior to Week 48 Visit: 
In the event that a subject discontinues the study prior to Week 48 visit, the site should 
use every reasonable effort to ensure that an Early Termination Visit is conducted. 
The following assessments should be performed: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
o 
 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
 
 
• 
 

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7.18.2. Post Week 48 to Week 240 Visit 
In the event that a subject discontinues the study after Week 48 and before Week 240 
visit, the site should use every reasonable effort to ensure that an Early Termination 
Visit is conducted. The following assessments should be performed: 
Recording of: concomitant medication, vital signs, AEs. 
The following procedures will be carried out: 
• Blood draw for: 
o Biochemistry and haematology 
o 
 
o 
 
o 
 
• Standard ophthalmic examination 
• CFP 
• FAF 
• OCT macula 
• 
 
• OCT-A if clinically indicated (if a subject converts to wet AMD) 
• FA if clinically indicated (if a subject converts to wet AMD). FA is only required 
if OCT/OCT-A images are inconclusive to rule out the presence of CNV. 
However, FA may also be performed prior to the OCT/OCT-A results being 
available, but this is not mandatory 
• 
Microperimetry. Note: microperimetry is only applicable at sites with a 
MAIA microperimeter 
• Visual acuity (BCVA and LLVA) using ETDRS 
• 
 
 

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8. STUDY PROCEDURES/EVALUATIONS 
8.1. Clinical evaluations 
8.1.1. 
Demographics 
Race, ethnicity, age (year of birth only), and gender will be captured as demographic 
data at screening. 
8.1.2. 
Medical History & Concomitant Medication Review 
Prior and concomitant medication as well as significant medical history (including all 
ocular history) will be reviewed and recorded in the eCRF. 
This information will comprise (and be updated throughout the study): 
• Documentation of presenting complaints and history 
• All current and prior ocular medical and surgical history 
• All current and prior significant general medical and surgical history 
• Pertinent family (e.g., related parents and children) and social history 
• Current medication use (ocular and other) and those used in past 90 days 
• Any drug allergy or contraindication to steroids  
8.1.3. 
Vital Signs 
Vital signs including heart rate, temperature, and blood pressure will be measured. 
Blood pressure (systolic and diastolic) is to be measured in triplicate after five minutes 
rest in a sitting position for the screening assessment only. The same method should 
be used throughout the study. Pulse will be assessed as a single measurement.  
8.1.4. 
Pregnancy Test 
Females of child-bearing potential are defined as those who have experienced 
menarche in the past 12 months and do not meet the criteria for women not of 
child-bearing potential. Women not of child-bearing potential are females who are 
permanently sterile (e.g., bilateral tubal ligation, hysterectomy, or bilateral 
oophorectomy) or post-menopausal. Post-menopausal is defined as 12 consecutive 
months with no menses without an alternative medical cause. 
Females of childbearing potential will undergo urine pregnancy testing at Visit 1 
(screening). In case the screening visit and the dosing day is more than 14 days apart, 
a urine pregnancy test will be repeated before surgery to exclude an early pregnancy. 
8.2. Laboratory Evaluations 
8.2.1. 
Clinical Laboratory Evaluations 
The anticipated volume of blood samples collected during the study from each subject 
will not exceed 250 mL (over approximately one year). Any remains from the safety 
laboratory samples will be disposed of after analyses. 
Blood samples for analysis of clinical chemistry and haematology variables will be 
collected at all specified visits and sent to the central laboratory.  

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8.2.2. 
Non-standard Assays 
Serum CFI Levels 
Serum CFI levels will be evaluated using a validated enzyme-linked immunosorbent 
assay. 
Genetic Testing for Complement Genotypes Associated with AMD  
Subjects entered into the study must have genotyping performed by a Sponsor-
approved laboratory, either through participation in a previous Sponsor study, or 
during the FOCUS screening period. 
 
 
 
 
 
  
 
 
 
8.2.3. 
Ophthalmic Procedures 
Standard Ophthalmic Examination 
Ophthalmological examinations in both eyes will be performed as follows: anterior 
segment examination including ocular inflammation assessment via slit lamp 

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biomicroscopy, IOP via Goldmann applanation tonometry, posterior segment and 
fundus examination via dilated indirect ophthalmoscopy.  
Slit lamp will be conducted on both eyes. The eyelids, cornea, conjunctiva, anterior 
chamber, iris/pupil and lens should be evaluated. Findings will be graded as normal, 
abnormal non-clinically significant, or abnormal clinically significant. Cataract will be 
graded using the AREDS clinical lens grading system (see Section 26.3). Intraocular 
pressure will be assessed in both eyes with a tonometer. 
Dilated indirect ophthalmoscopy will assess the vitreous, macula, choroid, optic nerve, 
retina and cup- to-disc ratio of both eyes. Findings will be graded as normal, abnormal 
non-clinically significant, or abnormal clinically significant. Indirect ophthalmoscopy will 
be performed per the Schedule of Assessments. 
Measurement of Geographic Atrophy 
GA area is measured by FAF. 
Prior to study start, sites will be qualified by a central reader to ensure fundus images 
fulfil the appropriate quality requirements. For consistency and to reduce variability, all 
images will be taken according to a study specific imaging protocol provided to all sites 
by the reading centre; all images will be reviewed and quantified by a central reader. 
The study specific imaging protocol is part of the GT005-01 Photographer Certification, 
Imaging, & Export Manual. 
Fundus Autofluorescence 
Fundus autofluorescence is a non-invasive retinal imaging modality used in clinical 
practice to provide a density map of lipofuscin, the predominant ocular fluorophore, in 
the RPE. 
Autofluorescence images of the fundus of both eyes will be obtained using the clinical 
site’s preferred ophthalmic imaging camera. Additional imaging of pertinent retinal 
regions can be performed at the discretion of the Investigator. 
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
 
Colour Fundus Photography 
Colour images of the fundus of both eyes will be obtained using the clinical site’s 
preferred ophthalmic imaging camera. Additional imaging of pertinent retinal regions 
can be performed at the discretion of the Investigator. 
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
Optical Coherence Tomography (Macula 
) 
Optical coherence tomography is a method of using low-coherence interferometry to 
determine the echo time delay and magnitude of backscattered light reflected off an 
object of interest. This method can be used to scan through the layers of a structured 
tissue sample such as the retina with very high axial resolution (3 to 15 μm), providing 
images demonstrating three-dimensional structure. Because of the unique optically 
clear pathway through the eye, OCT has been used most extensively for imaging 
disorders affecting the retina. 

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A series of horizontal raster scans centred on the fovea of each eye will be obtained 
with Heidelberg Spectralis (specific setting will be defined in the GT005-01 
Photographer Certification, Imaging, & Export Manual. 
Additional OCT imaging of pertinent retinal regions of the treated eye may be 
performed at the discretion of the Investigator. 
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
Optical Coherence Tomography-A 
Optical coherence tomography-A allows for non-invasive evaluation of retinal and 
choroidal vascular abnormalities that is useful as a diagnostic tool for Investigators to 
identify CNV which is an eligibility exclusion criterion. OCT-A may be performed as 
clinically indicated during the course of the study, for example, if a subject converts to 
wet AMD.  
If OCT-A is not available, other imaging modalities as described in the Central Imaging 
Manual may be utilised to assess for CNV. 
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
Fluorescein Angiography 
A contrast medium (Sodium Fluorescein) is injected into a vein in the subject’s arm. 
The dye travels quickly through the circulatory system and is photographed in black 
and white as it travels through the eye. The same camera used for fundus photography 
is employed in this procedure. Two filters are used to limit the image to the colour of 
light being emitted from the fluorescent dye. 
The normal progression of dye is interrupted by diseases of the choroid, retina, and 
retinal vasculature. 
Fluorescein angiography should be performed in the event, that the OCT/OCT-A 
images are inconclusive in order to rule out the presence of CNV. Fluorescein 
angiography may also be performed prior to the OCT/OCT-A result being available, 
however, this is not mandatory.  
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
Microperimetry 
Microperimetry, sometimes called fundus related perimetry, is a type of visual field test 
used to create a “retinal sensitivity map” of the quantity of light perceived in specific 
parts of the retina in people who have lost the ability to fixate on an object or light 
source.  
The combination of subjective (sensitivity map) and objective (retinography) data will 
be unified on a microperimetry map, allowing analysis of the retinal function before 
and after treatment. 
As microperimetry is an exploratory assessment it will be included at those sites who 
have the capability in this study; it is acknowledged that some subjects may not be 
able to perform this test because of limited ability to fixate.  

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Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
Visual Acuity: BCVA and LLVA using the ETDRS chart 
The BCVA of each eye will be performed by obtaining the subject’s manifest refraction 
and using the BCVA ETDRS methodology at 4 meters or 1 meter, or level of count 
fingers, hand motion or light perception.  
Low luminance visual acuity should be performed immediately after BCVA and 
involves placing a 2.0-log-unit neutral density filter over the front of each eye.  
Detailed instructions are part of the Investigator Site File. 
 
 
 
• 
. 
  
 
 
 
 
 
 
Additional functional assessments (microperimetry or standard perimetry) 
 
 
 
 
 
 
 
 
Additional microperimetry/perimetry should be collected either at the next scheduled 
visit or at an unscheduled visit if there is no upcoming planned study visit. If a standard 
perimeter is not available at the site, the Sponsor will assist with arranging transport 
of the subject to another location to perform the assessment. This additional safety 
assessment should be acquired at all future study visits (refer to the Central Imaging 
Manual for specific instructions for functional assessment collection). 
 
8.2.4. 
Historical FAF and OCT images 
 
If available, historical FAF and/or OCT images obtained within 1 year prior to 
enrolment will be reviewed by the Central Reading Centre to assess GA lesion size, 
with the purpose to obtain pre-treatment information on GA growth, to explore the 
natural history of disease progression.  

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Enrolled subjects will be asked if they are willing to consent to have historical FAF 
and/or OCT images that were obtained within 1 year prior to enrolment, if available, 
provided to the sponsor. This is optional and requires additional consent; the 
Investigator or designee will explain that the subject is under no obligation to provide 
this consent. If informed consent is given by a subject, the images will be provided to 
the Central Reading Centre and the historical lesion size will be measured and 
recorded. 
Detailed instructions are part of the GT005-01 Photographer Certification, Imaging, & 
Export Manual. 
 
8.3. Contraceptive Requirements 
Each subject will be reminded to use two forms of contraception (one of which being 
a barrier method) for 90 days for men and women of child-bearing potential.  
Male subjects  
Male subjects whose female partner(s) is (are) pregnant must use a condom from the 
time of the first administration of treatment or study medication until three months 
(90 days) following administration of the last treatment or dose of study medication. 
If the subject has undergone surgical sterilisation (vasectomy with documentation of 
azoospermia) a condom must be used. 
Male subjects must use acceptable methods of contraception if the male subject’s 
partner could become pregnant from the time of the first administration of treatment or 
study medication until three months following administration of the last treatment or 
dose of study medication. The acceptable methods of contraception are as follows:  
• Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository 
• Surgical sterilisation (vasectomy with documentation of azoospermia) and a 
barrier method (condom or occlusive cap (diaphragm or cervical/vault caps) 
used with spermicidal foam/gel/film/cream/suppository) 
• The female partner uses oral contraceptives (combination oestrogen/ 
progesterone pills), injectable progesterone or subdermal implants and a barrier 
method (condom or occlusive cap (diaphragm or cervical/vault caps) used with 
spermicidal foam/gel/film/cream/suppository) 
• The female partner has undergone documented tubal ligation (female 
sterilisation). In addition, a barrier method (condom or occlusive cap 
(diaphragm 
or 
cervical/vault 
caps) 
used 
with 
spermicidal 
foam/gel/film/cream/suppository) must be used 
• The female partner has undergone documented placement of an intrauterine 
device or intrauterine system and the use of a barrier method (condom or 
occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository) 
• True abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-

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ovulation methods) and withdrawal are not acceptable methods of 
contraception 
Female subjects  
Female subjects of childbearing potential must use medically acceptable methods of 
contraception from the time of the first administration of treatment or study medication 
until three months (90 days) following administration of the last treatment or dose of 
study medication for women of childbearing potential. 
Acceptable methods include:  
• A documented placement of an intrauterine device or intrauterine device and 
the use of a barrier method (condom or occlusive cap (diaphragm or 
cervical/vault caps) used with spermicidal foam/gel/film/cream/suppository) 
• Documented tubal ligation (female sterilisation). In addition, a barrier method 
(condom or occlusive cap (diaphragm or cervical/vault caps) used with 
spermicidal foam/gel/film/cream/suppository) should also be used 
• Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository 
• Oral contraceptives (combination oestrogen/progesterone pills), injectable 
progesterone or subdermal implants and the use of a barrier method (condom 
or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal 
foam/gel/film/cream/suppository) 
• True abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception 
 
 
 

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9. ADVERSE EVENT REPORTING 
9.1. Definitions 
All AEs will be captured from the time the subject provides written informed consent 
and monitored throughout the study. 
Adverse Event: Untoward medical occurrence in a subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavourable and unintended sign (including laboratory 
abnormal finding), system or disease temporally associated with the use of the 
medicinal product, whether or not considered as related to GT005. 
Adverse Drug Reaction: Untoward and unintended responses to GT005 related to 
any dose administered. 
All AEs judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. 
The expression “reasonable causal relationship” means to convey in general that there 
are facts or evidence meant to suggest a causal relationship. 
Serious Adverse Event: Untoward medical occurrence or effect that at any dose falls 
in one or more of the following categories: 
• Results in death 
• Is life-threatening 
• Requires hospitalisation or prolongation of existing inpatient hospitalisation. 
Hospitalisation refers to a situation whereby an AE is associated with 
unplanned overnight admission into hospital. 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is a medically significant AE 
Adverse Events of Special Interest (AESI): An AESI (serious or non-serious) is one 
of scientific and medical concern specific to the Sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor 
can be appropriate. 
 
  
 
 
 
 
 
 

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It is anticipated that there may be transient decreases to visual acuity related to the 
subretinal injection surgical procedure. A transient visual loss may be observed in the 
first days post-surgery due to bleb-related foveal detachment, if performed. Transient 
surgery-related events of decreases in visual acuity are defined as decreases 
occurring in close temporal association (within <24 hours) with the surgical 
administration of the study medication, and which are resolving at Week 1 (Visit 3) 
post-surgery. 
Additionally, there is a known risk of cataract associated with any vitrectomy 
procedure. A published review from [Feng 2014] shows cataract to be common 
following pars plana vitrectomy with about 40% of patients requiring a cataract 
extraction over the following 2 years.  
These do not require reporting as AESIs.  
Device Specific Adverse Events: 
Serious injury means an injury or illness that: 
1. Is life-threatening, 
2. Results in permanent impairment of a body function or permanent damage to a 
body structure, or 
3. Necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure. 
Permanent means irreversible impairment or damage to a body structure or 
function, excluding trivial impairment or damage. 
For the reporting purposes of this study, a serious injury related to the device is 
considered an SAE. 
9.2. Expectedness 
An expected adverse reaction is where the nature or severity of the AE is consistent 
with the applicable product information (IB for an unapproved investigational product 
or SmPC or approved Package Insert for an authorised product), otherwise it is 
considered unexpected. 
9.3. Intensity of Adverse Event 
The Investigator will use the adjectives MILD, MODERATE, or SEVERE to describe 
the maximum intensity of the AE. 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 

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9.4. Causality Assessment 
When assigning relatedness of the AE, consideration will be given to whether there is 
a plausible relationship to either the study medication or the surgical procedure. For 
Cohorts 4 to 7, AEs deemed related to the surgical procedure will be considered to be 
related to either the transvitreal procedure or to the suprachoroidal cannulation 
procedure with the Orbit SDS, depending on the route of GT005 administration. AEs 
related to the suprachoroidal cannulation procedure with the Orbit SDS are considered 
device -related events. 
AE severity and relationship to the study medication or the surgical procedure will be 
assessed at the site by the Investigator or a medically qualified designee. 
The following are definitions of relatedness that will be used in this study: 
Related: reports including good reasons and sufficient information (e.g., plausible time 
sequence, dose-response relationship, pharmacology, mechanics of surgical 
procedure) to assume a causal relationship to the study medication or the surgical 
procedure. In the sense that it is plausible, conceivable or likely. 
Not related: reports including good reasons and sufficient information (e.g., 
implausible time sequence and/or attributable to concurrent disease or other drugs) to 
rule out a causal relationship to the study medication or the surgical procedure with 
GT005 administration. 
Unknown: there is insufficient information to assess plausibility of causal relationship 
to the study medication or the surgical procedure. 
9.5. Action Taken Regarding the Study Drug 
The action taken regarding study drug must be described by selecting one of the 
following: 
• Dose not changed – no action taken 
• Drug withdrawn – not administered 
• Dose reduced – partially administered 
• Unknown/not applicable 
9.6. Outcome 
Each AE must be rated by selecting one of the following: 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered with sequelae/resolved with sequelae 
• Fatal 
• Unknown 

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9.7. Recording Adverse Events 
It is the responsibility of the Investigator to collect all AEs (both serious and 
non-serious). 
All AEs occurring during the study must be documented on the appropriate section of 
the eCRF. 
If an AE is considered serious, it must also be recorded on the Serious Adverse Event 
Form provided separately. 
9.8. Reporting Serious Adverse Events and Adverse Events of 
Special Interest to the Sponsor 
All AESIs and SAEs occurring from informed consent through to the long-term 
follow-up section of the study, or if the subject is not taking part in the long-term 
follow-up part of the study, until resolution of the event will be reported immediately 
(within 24 hours) by the Investigator, Contract Research Organisation (CRO) and/or 
Sponsor to the 
 Safety team, regardless of causal relationship. The 
applicable form (electronic data capture or back-up form) must be filled in by a member 
of the research team and kept in the Investigator site file. 
All SAEs/AESIs must be reported in the eCRF. Alternatively, if the eCRF cannot be 
accessed, please contact 
 by telephone, fax or email: 
 SAE hotline – United States: 
Telephone: 
 
Fax: 
 
e-mail: 
 
 
OR 
 SAE hotline – Europe: 
Telephone: 
 
Fax: 
 
e-mail: 
 
 

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Where the Investigator requires advice regarding the handling of SAEs/AESIs the 
contact in case of emergency is: 
, dial 3 (United States) 
 
OR 
 
 (Europe) 
 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to 
Medpace Clinical Safety within 24 hours of knowledge of the event. Medpace Clinical 
Safety will then provide the Investigator/site the Exposure In Utero (EIU) form for 
completion. The Investigator/site must complete the EIU form and fax/email it back to 
Medpace Clinical Safety. The pregnancy should be followed until the outcome of the 
pregnancy, whenever possible. Once the outcome of the pregnancy is known, the 
follow-up EIU form should be completed and faxed/emailed to 
 Clinical 
Safety. 
Gyroscope Therapeutics will report all relevant safety information about suspected 
unexpected serious adverse reactions (SUSARs) (and any new safety information that 
would adversely affect the safety of subjects or the conduct of the study) for the 
product under investigation to the Competent Authorities, Institutional Review Boards 
(IRBs)/Research Ethics Committee (RECs), Investigators and DSMB for the duration 
of the study as required by country-specific regulations.  
 
In addition, any new safety information that would adversely affect the safety of 
subjects or the conduct of the study will be reported by Gyroscope to the Competent 
Authorities, Research Ethics Committees (RECs), DSMB and Investigators. If the 
study is to be suspended as a result of a SUSAR, or due to any urgent safety measure 
taken, Competent Authorities and RECs will be notified as soon as possible and within 
three days of the decision.  
 
For study centres in the United States, Investigational New Drug safety reports will be 
submitted directly to the Investigators. It is the Investigators’ responsibility to notify 
their IRBs/RECs in a timely manner. Gyroscope will submit Safety Reports to the 
applicable Competent Authorities and IRBs/RECs as required by country-specific 
regulations. 
  
 
 
 
 
 
  
 
 
 
 

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10. 
DATA MANAGEMENT 
Data will be recorded on an eCRF by the Investigator (or designee). The database, 
data entry and electronic checks will be developed using a Clinical Database 
Management System. Computerised data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency and 
completeness of the data. An electronic audit trail system will be used to track all data 
changes in the database. 
Data clarification queries will be generated electronically in order to clarify any issues 
which arise regarding the data entered into the eCRF and database. 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary; medications will be coded using the World Health 
Organisation Drug Dictionary. 
10.1. Trial Documentation and Trial Confidentiality 
10.1.1. 
Trial Documentation, eCRFs and Document Keeping 
The Investigator must generate and maintain adequate records (subject medical 
records, eCRFs, source documents) to enable the conduct of this study to be fully 
documented. Each subject enrolled into the study must have an eCRF completed and 
the eCRF must be reviewed and signed off by the Investigator. This applies to those 
subjects who failed to complete the study (even during the pre-surgery period). eCRFs 
are to be completed either at the time of the subject’s visit or as soon as possible after 
the visit so that they always reflect the latest observations on the subjects participating 
in the study. The Investigator must verify that all data entries in the eCRFs are accurate 
and correct. The nature and location of all source documents will be identified to 
ensure that all sources of original data required to complete the eCRF are known to 
the investigational staff and are accessible for verification by the clinical monitor. If 
electronic records are maintained, the method of verification must be discussed with 
the investigational staff. A source data verification log will be prepared by the CRO. 
This will describe the proportion of eCRF data that will be verified by the monitor 
against the subjects’ medical records and source data.  
The Sponsor recommends that the author of an entry in the source documents be 
identifiable. Direct access to source documentation (medical records) must be allowed 
for the purpose of verifying that the data recorded on the eCRF are consistent with the 
original source data. 
If data are recorded directly into the eCRF, there should be, at a minimum, an entry in 
the medical record that each of the assessments was performed; who performed it 
and the date it was done. 
The eCRF will be compared with the source documents to ensure that there are no 
discrepancies between critical data. All entries, corrections, and alterations are to be 
made by the responsible Investigator or an authorised member of the investigational 
staff. 
Data clarification and query resolution will be conducted on an ongoing basis by the 
monitor and the contract data management company. The Sponsor will have overall 
responsibility for the data. 
The Investigator must be aware of their responsibility to retain subject identification 
codes in line with regulatory requirements after completion or discontinuation of the 

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study. If a subject withdraws from the study, then the reason must be noted in the 
eCRF. If a subject ceases treatment because of an AE, reasonable efforts must be 
made to clearly document the outcome. 
The Investigator will allow authorised Sponsor personnel, auditors and regulatory 
authorities direct access to the subjects’ medical records.  
Copies of protocols, eCRF page/printouts, originals of test results, reports, drug 
dispensing logs, correspondence, records of informed consent or other documents 
pertaining to the conduct of the study must be kept on file by the Investigator in line 
with regulatory requirements or for the period of time specified by local law for the 
preservation of hospital subject documents, whichever is longer. No study documents 
should be destroyed without prior written agreement between the Sponsor and the 
Investigator. Where storage at the centre is limited, the Sponsor may make 
arrangement for documents to be stored at an independent data archiving facility on 
behalf of the Investigator. Should the Investigator wish to assign the study records to 
another party, or move them to another location, the clinical trial monitor must be 
consulted.  
10.1.2. 
Confidentiality of Trial Documents and Subject Records 
The Investigator must ensure the subjects’ anonymity is maintained. On eCRFs or 
other documents submitted to the Sponsor (or designee), subjects must NOT be 
identified by their names but by an identification code (usually their study number). 
The Investigator will be responsible for maintaining a separate log of subjects’ codes, 
names and unique identifiers. This log will be maintained as required by applicable 
regulatory requirements. Documents not for submission to the Sponsor or designee, 
e.g., subjects’ written consent forms, must be maintained by the Investigator in strict 
confidence. Genetic testing will occur prior to surgery but to ensure subject 
confidentiality, the distribution of these data will be carefully controlled.  
 
 

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11. 
STATISTICAL ANALYSIS PLAN 
A detailed statistical analysis plan (SAP) will be produced after having finalised the 
protocol and before the database is locked prior to analysis. 
11.1. Sample Size 
As this is a FIH exploratory Phase I/II study, no formal sample size has been 
calculated.  
11.2. Population for Analysis 
Two analysis sets will be defined. The Safety Analysis Set (SAF) will include all 
subjects who have undergone surgery and received GT005. The SAF will be used for 
analysis of safety and laboratory data. The Full Analysis Set (FAS) will include all 
subjects in SAF who have baseline and at least one post-baseline value of GA area 
size via FAF in the study eye. The FAS will be used for analysis of efficacy data.    
11.3. Statistical Analysis 
The detailed statistical analyses will be outlined in the SAP. 
The main analysis will be performed at the conclusion of the study (Week 240), after 
which a clinical study report (CSR) will be prepared. Interim analyses may be 
considered to help inform internal development decision points for GT005, in which 
case the details will be pre-specified in the SAP prior to conducting the analysis. 
Additionally, a safety focused analysis will be conducted to enable the independent 
data review by a DSMB after three subjects in Cohorts 1 to 3 and Cohort 5 have 
completed the 5-week post-surgery visit. Additional DSMB meetings may be held as 
needed or as requested by the DSMB members. Full details can be found in the DSMB 
Charter. 
Analyses of data involving the Orbit SDS is US-specific. 
For the main statistical analysis and CSR, all efficacy (anatomical and functional visual 
outcomes) and safety data will be listed and summarised using descriptive statistics 
by dose and route of administration, and by assessment (Visits 1 to 8). The Long-term 
follow-up data (Visits 9 to 13) will be reported separately using descriptive statistics by 
dose and route of administration and by assessment. Additionally, for all ocular 
evaluations and tests, and ocular AEs, where appropriate these will be additionally 
presented by eye (Treated [Study Eye]/Untreated [Fellow Eye]). The descriptive 
summary for the categorical variables will include subject counts (n) and percentages 
and, if appropriate, frequency of events. The descriptive summary for the continuous 
variables will include counts (n), means, medians, standard deviations and minimum 
and maximum values. Where possible, all data from subjects who withdraw 
prematurely from the study will be included in any presentations. Further details on the 
handling of withdrawals and/or missing data will be specified in the SAP. 
Subgroup analyses will be performed, if appropriate, to evaluate some of the efficacy 
endpoints across subgroups defined by genetic classification: e.g., a rare variant 
resulting in CFI haploinsufficiency and those without. 

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Graphical displays appropriate to the types of data may be used to present any 
important findings. 
Any deviations from the planned analyses detailed in the protocol will be documented 
in the SAP and final CSR. If the study is prematurely discontinued, all available data 
will be listed and a review will be carried out to determine which statistical analyses 
are considered appropriate. 
11.3.1. Demographics and Baseline Characteristics: 
Surgical details and measures at baseline including: demographics, medical/surgical 
history, concomitant medication, laboratory safety, and urine pregnancy testing will be 
summarised descriptively by dose and route of administration. No formal comparisons 
between Cohorts will be made. Assessments made at screening/baseline and also 
post-surgery will only be included in their respective safety and efficacy tables, 
together with post-baseline assessment values. 
A medication given prior to the injection of study drug during surgery will be classified 
as a prior medication. A medication given with or after the injection of study drug will 
be classified as concomitant. Prior medications continuing during the study will be 
labelled accordingly in the listings. 
Verbatim medical/surgical history terms will be coded (to preferred terms) using 
terminology from MedDRA. Medications will be coded using the World Health 
Organisation Drug Dictionary to Anatomical Therapeutic Chemical classification level 
2 (therapeutic main group) and preferred term. 
Additionally, the last visual acuity values measured using the BCVA ETDRS prior to 
surgery will be presented with the baseline data by dose and route of administration 
and by eye (Treated [Study Eye]/Untreated [Fellow Eye]). Genetic testing will also 
occur prior to surgery but to ensure subject confidentiality, the distribution of these 
data will be carefully controlled. Further details of the procedures required for 
maintaining the subject’s genetic profile confidentiality will be discussed in greater 
detail in the SAP. 
11.3.2. Efficacy 
Efficacy assessments to evaluate the anatomical and functional visual outcomes 
involve: GA area size (via FAF), 
 
, macular mean sensitivity via Microperimetry, 
 For continuous 
efficacy variables the change from baseline will be derived and presented together 
with actual values over time (visit) by dose and route of administration and by eye 
(Treated [Study Eye]/Untreated [Fellow Eye]). Categorical variables from any ocular 
evaluations will be presented by classification over time (visit) by dose and route of 
administration and by eye (Treated [Study Eye]/Untreated [Fellow Eye]). 
 
  
The GA area size data will be compared to historical data on natural disease 
progression, including pre-treatment data from FOCUS subjects if available. 

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11.3.4. Safety 
The assessment of safety will be based primarily on the following: AEs, ophthalmic 
examination, BCVA/LLVA scores (ETDRS), vital signs, laboratory safety (biochemistry 
and haematology), and 
 
 Adverse Events 
Adverse events will be collected and recorded throughout the study and verbatim AE 
terms will be coded (to preferred terms) using terminology from MedDRA. 
A TEAE is defined as an AE that is first identified, or is identified to worsen in intensity, 
on or after the subject receives the study medication during surgery. 
The incidence, maximum intensity, and relationship to study medication or procedure 
of TEAEs will be summarised by system organ class and preferred term, according to 
dose and route of administration, as appropriate, and classified as systemic or ocular 
(Treated [Study Eye]/Untreated [Fellow Eye] or Both eyes). 
All AEs, SAEs, AESIs, AEs leading to discontinuation, and deaths will be listed.  
11.3.4.1. 
Ophthalmic Examination 
Ophthalmic examinations will be displayed as continuous (actual and change from 
baseline values), or categorical data as appropriate by dose and route of 
administration, and by eye (Treated [Study Eye]/Untreated [Fellow Eye]) for each 
assessment. For continuous data evaluations, differences and change from baseline 
differences between Treated and Untreated eyes will also be presented by dose and 
route of administration for each assessment. 
11.3.4.2. 
Visual Acuity (BCVA and LLVA) 
Will be presented as for continuous ophthalmic examinations by eye. 
11.3.4.3. 
Laboratory Tests 
For haematology and chemistry laboratory test results, descriptive statistics and 
change from baseline over time will be summarised by dose and route of 
administration. All laboratory test results including urinalysis will be listed. 
11.3.4.4. 
Vital Signs 
For blood pressure and pulse rate, and body temperature, descriptive statistics and 
change from baseline over time will be summarised by dose and route of 
administration.  
 
 
 
 
 
 

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12. 
INSTITUTIONAL REVIEW BOARD (IRB)/ RESEARCH ETHICS 
COMMITTEE (REC)  
This study must be conducted in compliance with IRBs/RECs, informed consent 
regulations, the Declaration of Helsinki, International Council for Harmonisation (ICH) 
GCP Guidelines, and the FDA, 21 CFR Part 11, Electronic Records, Electronic 
Signatures, and FDA, Guidance for Industry: Computerised Systems Used in Clinical 
Trials. 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the Investigator/institution should have written and dated 
approval/favourable opinion from the IRB/REC for the study protocol/amendment(s), 
written informed consent form, any consent form updates, subject emergency study 
contact cards, subject recruitment procedures (e.g., advertisements), any written 
information to be provided to subjects and a statement from the IRB/REC that they 
comply with GCP requirements. The IRB/REC approval must identify the protocol 
version as well as the documents reviewed. 
After IRB/REC approval, changes will require a formal amendment. Once the study 
has started, amendments should be made only in exceptional circumstances. 
Changes that do not affect subject safety or data integrity are classified as 
administrative changes and generally do not require ethical approval. If ethically 
relevant aspects are concerned, the IRB/REC must be informed and, if necessary, 
approval sought prior to implementation. Ethical approval on administrative changes 
will be obtained if required by local/site IRB/REC. 
The Investigator should provide written reports to the REC annually or more frequently 
if requested on any changes significantly affecting the conduct of the study and/or 
increasing risk to the subjects. 
 

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13. 
REGULATORY REQUIREMENTS 
The study will be authorised by the Competent Authority. 
Enrolment of subjects will not start until approval has been received from both the 
IRB/REC and Competent Authorities. 
The study will be conducted in accordance with the Declaration of Helsinki, GCP and 
all other national requirements. 
 

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14. 
PROTOCOL AMENDMENTS 
14.1. 
Protocol Amendments and Protocol Deviations 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion of a written amendment by the IRB/REC, except 
when necessary to eliminate immediate safety concerns to the subjects or when the 
change involves only logistics or administration. The Investigator and the Sponsor will 
sign the protocol amendment. 
In the event, that an amendment to this protocol is required, this will be classified into 
one of the following three categories: 
• Administrational changes are those that are not considered ‘substantial’ 
(e.g., administrative changes), and as such are not required to be notified to the 
IRBs/RECs or Competent Authority but are contained in the protocol under a 
subsequent notification of a substantial amendment 
• Substantial amendments are those considered ‘substantial’ to the conduct of 
the clinical study where they are likely to have a significant impact on: 
o the safety or physical or mental integrity of the subjects 
o the scientific value of the study 
o the conduct or management of the study, or the quality or safety of GT005 
used in the study 
Substantial amendments must be notified to the IRB/REC and Competent Authority. 
Prior to implementation, documented approval must be received from the IRB/REC. 
• Urgent amendments are those that require urgent safety measures to protect 
the study subjects from immediate hazard, and as such may be implemented 
immediately by the Sponsor with subsequent IRB/REC and Competent 
Authority notification, forthwith 
14.2. 
Protocol Deviations and Exceptions 
A protocol deviation is non-adherence to protocol specific study procedures or 
schedules or the requirements of ICH-GCP that have been identified retrospectively. 
Protocol deviations are not acceptable from a regulatory perspective and any deviation 
not supported by an amendment will be considered a potential breach of GCP. 
Deviations from the protocol should only occur when necessary to eliminate immediate 
hazards to the subjects.  
Protocol deviations will be identified and recorded by investigative site personnel on 
the eCRF, and by the study monitor in the Monitoring Visit Reports and/or the 
electronic data capture (EDC) system. Protocol deviations must be reported to 
Competent Authority and the IRB/REC as per their local or national guidelines. 
As a matter of policy, the Sponsor will not grant exceptions to protocol specific entry 
criteria to allow subjects to enter a study. If such an action is considered ethically, 
medically, and scientifically justified for a particular subject, prior approval from the 
Sponsor and the responsible IRB/REC, in accordance with the standard operating 
procedure, is required before the subject will be allowed to enter the study. If 
investigative site personnel learn that a subject who did not meet protocol eligibility 
criteria was entered in a study, they must immediately inform the Sponsor. 

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15. 
INFORMED CONSENT 
It is the responsibility of the Investigator to obtain written consent from each subject, 
or from the subject’s legal representative prior to any study related procedures taking 
place. 
If the subject and his/her legal representative are unable to read, the informed consent 
will be obtained in the presence of an impartial witness, e.g., a person independent of 
the study who will read the informed consent form and the written information for the 
subject. 
Consent must be documented by the subject’s dated signature. The signature 
confirms that the consent is based in information that has been understood. Moreover, 
the Investigator must sign and date the informed consent form.  
Each subject’s signed informed consent must be kept on file by the Investigator. One 
copy must be given to the subject. 
 

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16. 
DIRECT ACCESS TO SOURCE DOCUMENTATION/DATA 
The Investigator must permit study-related monitoring, audits, IRB/REC review or 
regulatory inspection, providing direct access to source data/documents. 
 

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17. 
STUDY MONITORING 
It is understood that the independent study monitor(s) will contact and visit the 
Investigator/clinical site before the study, regularly throughout the study and after the 
study has been completed. At these visits the monitor(s) will inspect various study 
records; eCRFs, Investigator Site File and source data, provided that subject 
confidentiality is respected. The Investigator and/or site staff will be expected to be 
available if requested by the monitor. 
 

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18. 
QUALITY ASSURANCE 
The Sponsor may perform an audit at any time according to the Sponsor’s Standard 
Operating Procedure in order to verify whether the study is being conducted according 
to GCP. 
 

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19. 
INSURANCE 
Appropriate insurance cover has been secured in favour of subjects participating in 
clinical studies. The cover is provided to the subject on terms and conditions of the 
clinical trial insurance. Insurance cover exists for health damages resulting from 
measures carried out in connection with the clinical study. 
 

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20. 
CONFIDENTIALITY 
All study documents are provided by the Sponsor in confidence to the Investigator and 
appointed staff. No study material may be disclosed to any party not directly involved 
in the study without written permission from the Sponsor. 
The Investigator must assure that subject’s anonymity will be provided. The 
Investigator will keep a separate list with at least the initials, the subject’s study 
number, names, addresses and telephone numbers. The Investigator will maintain this 
for as long as requested by the Sponsor. 
 

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21. 
PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any 
time. Should this be necessary, the procedures for an early termination or temporary 
halt will be arranged after consultation with all parties. 
All subjects participating in the clinical study will receive from the Investigator an alert 
card, which has been previously agreed by the Sponsor and approved by the 
IRB/REC, containing at minimum the name of the subject, the Investigator contact 
number and information regarding the medical treatment received. 
Where follow-up after the end of the study is required, in particular when this occurs 
over a long-term, the Sponsor will ensure that there is a process in place for follow-up 
of the subjects treated with the product even in cases where the product development 
is discontinued or the (former) Sponsor ceases to exist as a legal entity. 
This process will be achieved by: 
• Appropriate information about follow-up of the subjects after the end of the 
clinical study provided to healthcare establishments that served as centres for 
the particular clinical study 
• Websites/phone-lines that provide data/consultation in case of complications 
• Subject alert cards that inform treating physicians about the product used, and 
any independent registries or other sources of data available in case of 
safety/efficacy issues, and of the need to inform the national Competent 
Authority, the investigational sites and the Sponsor in the event of certain 
serious adverse reactions. These alert cards should contain at minimum the 
name of the subject, a physician contact number and information regarding the 
medical treatment received. They should have been previously agreed by the 
Sponsor and approved by the IRB/REC. This may be the same as the one used 
for the clinical study if changes or additional information is not required to 
address further follow-up after the end of the study 
 

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22. 
RECORD RETENTION 
After completion of the study, all documents and data relating to the study will be 
securely archived by the Investigator in a secure study file. 
Essential documents must be retained for at least thirty years after clinical use. It is 
the responsibility of the Sponsor to inform the Investigator of when these documents 
can be destroyed. The Investigator must contact the Sponsor before destroying any 
study-related documentation. In addition, all subjects’ medical records and other 
source documentation will be kept for the maximum time permitted by the institution. 

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23. 
PUBLICATION OF RESULTS 
No information provided by the Sponsor to the Investigators, DSMB or Study Steering 
Committee members for the purposes of performing or monitoring the study, will be 
published, or passed on to a third party, without prior written approval by the Sponsor.  
The detailed procedures for publications and data presentations are set out in the 
clinical trial agreement entered into with the Sponsor (or designee) in connection with 
this study. 
 

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24. 
STUDY COMMITTEES 
24.1. DATA SAFETY MONITORING BOARD 
Composition 
A DSMB will be formed to review all safety data at predetermined intervals during the 
study. Additional DSMB meetings may be held as needed or as requested by the 
DSMB members. The DSMB will comprise of at least three individuals who 
cumulatively have the clinical and medical expertise to monitor the safety of subjects 
in the clinical study and will include a minimum of one clinician expert in the 
management of AMD and clinical immunology. The DSMB will be chaired by one of 
the clinical experts who will attend all meetings. No DSMB member will be an 
Investigator in this study. 
Roles and Responsibilities of DSMB 
The roles and responsibilities of the DSMB are defined in the DSMB Charter, which 
include, but are not limited to: 
• Monitoring and reviewing all safety issues relative to the conduct of the study 
• Ensuring the protection and safety of subjects participating in the study 
• Recommending dose escalation in accordance with available safety data and 
study stopping rules 
• Recommending a different BCVA threshold for entry into the study 
• Providing recommendations to continue, modify the design, suspend or 
terminate the study depending upon emerging safety data 
• Communicating other recommendations or concerns as appropriate 
Dose Escalation 
• The DSMB will meet after the third subject has been enrolled (recruitment and 
treatment will continue – there will be no study hold) and provided Week 5 data 
in Cohorts 1 to 3, and in Cohort 5 
• If treatment has been tolerated and stopping rules have not been met, the 
DSMB will recommend to Gyroscope that enrolment of the next study Cohort 
can commence 
• Screening of potential subjects will be allowed prior to the DSMB meeting and 
decision, but treatment must not be administered to subjects in the higher dose 
group until the outcome of the DSMB recommendation has been provided in 
writing to Gyroscope  
Change to Inclusion Criteria 
The DSMB will meet after the third subject has been enrolled (recruitment and 
treatment will continue – there will be no study hold) and the possibility of raising the 
BCVA threshold for inclusion in the study at the respective dose-level will be assessed 
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DSMB Stopping Rules 
The DSMB will review the study data and recommend stopping dose escalation if any 
toxicity is evident within five weeks (Visit 4) of treatment, that is considered related to 
study medication or route of administration and that has: 
• Significantly and/or likely permanently reduced the subjects remaining vision 
• Been life-threatening 
• Occurs in one or more subjects in the same Cohort and would be considered 
severe enough to outweigh the potential benefits of the study medication 
In addition to the prescheduled meetings, the DSMB may be called upon at any time 
during the study to review immediate safety outcomes and/or concerns as they arise.  
Details regarding the DSMB mission and content of the DSMB data safety reviews will 
be specified in the DSMB charter. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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25. 
REFERENCES 
Access Economic Report 2010. The Global Economic Cost of Visual Impairment. 
Report by Access Economics Pty Limited for AMD Alliance International. 
Anderson. D. H, Radeke. M. J, Gallo, N. B, et al. The pivotal role of the complement 
system in aging and age-related macular degeneration: Hypothesis re-visited. 
Progress in Retinal and Eye Research 2010; 29: 95-112. 
Banin E. Abstract PA03: “Phase 1/2a Study of Subretinally Transplanted Human 
Embryonic Stem Cell-Derived RPE Cells in Advanced Dry-Form AMD Patients”. 
American Academy of Ophthalmology Annual Meeting 14-Oct-2019. 
Botquin, V., Cid-Arregui, angel, and Schlehofer, J.R. Adeno-associated virus type 2 
interferes with early development of mouse embryos. J. Gen. Virol. 1994; 75, 2655–
2662. 
Chakravarthy. U, Wong. T.Y, Fletcher. A, et al. Clinical risk factors for age-related 
macular degeneration: a systematic review and meta-analysis. BMC Ophthalmology 
2010, 10:31. 
Chang S. LXII Edward Jackson lecture: open angle glaucoma after vitrectomy. Am J 
Ophthalmol. 2006;141(6):1033-1043. 
Chew E, et al. Evaluation of the Age-Related Eye Disease Study Clinical Lens 
Grading System AREDS Report No. 31. Ophthalmol 2010; 117: 2112–2119. 
Couto, L., Parker, A., and Gordon, J.W. Direct Exposure of Mouse Spermatozoa to 
Very High Concentrations of a Serotype-2 Adeno-Associated Virus Gene Therapy 
Vector Fails to Lead to Germ Cell Transduction. Hum. Gene Ther. 2004; 15, 287–291. 
FDA Briefing Document, Advisory Committee Meeting, October 12, 2017, BLA 
125610, Voretigene Neparvovec, Spark Therapeutics, Inc. (FDA Website) 
Feng H, Adelman RA .Cataract formation following vitreoretinal procedures. Clinical 
Ophthalmology Volume 2014:8 Pages 1957—1965 
Ferris. F. L, Wilkinson. C. P, Bird. A, et al. Clinical Classification of Age-related Macular 
Degeneration. Ophthalmology 2013; 120 (4): 844-851. 
Fritsche. L. G, Igl. W, Cooke Bailey. J. N, et al. A large genome-wide association study 
of age-related macular degeneration highlights contributions of rare and common 
variants. Nature Genetics 2016; 48 (2): 134-143. 
Ginn, S.L., Amaya, A.K., Alexander, I.E., Edelstein, M., and Abedi, M.R. (2018). Gene 
therapy clinical trials worldwide to 2017: An update. J. Gene Med. 20, e3015. 
Gleeson. P.J, Wilson, V, Cox. T.E, et al. Chromosomal rearrangement—A rare cause 
of complement factor I associated atypical haemolytic uraemic syndrome. 
Immunobiology 2016; 221; 1124–1130 
Heier J. S, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients 
with advanced neovascular age-related macular degeneration: a phase 1, open-label 
trial. Lancet. 2017; 390(10089): 50-61. 
Heier J. S, Ho A.C, Samuel M.A, et al. Safety and Efficacy of Subretinally Administered 
Palucorcel for Geographic Atrophy of Age-related Macular Degeneration: Phase 2b 

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Study. 
Ophthalmology 
Retina. 
2019 
In 
Press: 
DOI: 
https://doi.org/10.1016/j.oret.2019.11.011 
Jonasson. F, Fisher. D. E, Eiriksdottir. G, et al. Five-year incidence, progression and 
risk factors for age-related macular degeneration: The Age, Gene/Environment 
Susceptibility Study. Ophthalmology. 2014; 121(9): 1766–1772. 
Kavanagh. D, Yu. Y, Schramm. E, et al. Rare genetic variants in the CFI gene are 
associated with advanced age-related macular degeneration and commonly result in 
reduced serum factor I levels. Human Molecular Genetics, 2015, Vol. 24, No. 13 3861–
3870 
Kersey, J., Broadway, D. Corticosteroid-induced glaucoma: a review of the literature. 
Eye 2006; 20, 407–416. 
Lachmann. P. J, Lay. E, Seilly. D. J, et al. Further studies of the down-regulation by 
Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells 
as a source of CR1 on sera of different complotype. Clinical and Experimental 
Immunology 2016; 183: 150–156. 
MacLaren. R.E, Groppe. M, Barnard. A.R, et al. Retinal Gene Therapy in Patients with 
Choroideremia: Initial Findings from a Phase 1/2 Clinical Trial. Lancet 2014; 383 
(9923): 1129–1137. 
Mandava, N., Tirado, V., Geiger, M., Patnaik, J., Frazer-Abel, A., Lynch, A., Mandava, 
N., Palestine, A., Holers, M., Wagner, B., et al. (2019). A0180: Plasma and Vitreous 
Complement Levels in Humans with Proliferative Diabetic Retinopathy.  
Mingozzi, F., and High, K.A. Immune responses to AAV vectors: overcoming barriers 
to successful gene therapy. Blood 2013; 122, 23. 
NIH: Age-related macular degeneration. National Eye Institute. June 2015. Available 
from: 
https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-
educators/eye-health-data-and-statistics/age-related-macular-degeneration-amd-
data-and-statistics [Last accessed: February 2020]. 
Provost N, Le Meur G, Weber M, et al. Biodistribution of rAAV vectors following 
intraocular administration: evidence for the presence and persistence of vector DNA 
in the optic nerve and in the brain. Mol Ther. 2005;11(2):275-83. 
Russell. S, Bennett. J, Wellman. J.A, et al. Efficacy and safety of voretigene 
neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal 
dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet 2017; 
http://dx.doi.org/10.1016/S0140-6736(17)31868-8. 
www.clinicaltrials.gov. NCT03846193. Available from: 
https://clinicaltrials.gov/ct2/show/NCT03846193?term=GT005-01&draw=2&rank=1 
[Last accessed: Jan, 2022]. 
Xue K, Groppe M, Salvetti AP and MacLaren RE. Technique of retinal gene therapy: 
delivery of viral vector into the subretinal space. Eye (2017) 31, 1308–1316. 
 

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26. 
 APPENDICES 
26.1. Early Treatment Diabetic Retinopathy Study Scale - Example 
 
 

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26.3. AREDS Clinical Lens Grading System 
Overview 
The AREDS developed the Clinical Lens Grading System for grading the presence 
and severity of nuclear, cortical and posterior subcapsular (PSC) lens opacities (the 
three main types of age-related cataract) in a clinical setting. The system was 
designed to require minimal examiner training for persons already proficient in the use 
of the slit lamp. 
General Instructions 
Dilation – Pupils should be dilated to at least 5mm. 
Grading of opacities – the lenses are examined at the slit lamp with 10x magnification 
for the presence and severity of the types of lens opacity: Nuclear, Cortical and 
Posterior Subcapsular. For each type of opacity the examined lens will be compared 
to a series of three reference standard photographs combined onto one print. The 
severity of opacity witnessed of the lens being assessed will be determined to equal 
the opacity on one of the three reference photographs or have an opacity which falls 
in between two of the reference standard photographs.  
Grading of Nuclear sclerosis  
Nuclear Landmarks - In the normal or non-sclerotic lens, the “nucleus” consists of a 
central dark interval (sulcus), adjacent bean-shaped brighter areas (lentils—one 
anterior and one posterior to the sulcus), and brighter curved bands (lamellae, or 
nuclear surface bands) anterior and posterior to the lentils and separated from them 
by narrow dark bands.-Although nuclear sclerosis standard 1 shows signs of moderate 
opalescence, many of these features are visible. 
For grading the severity of nuclear sclerosis two factors are considered:  
I. 
The optical density of the nuclear landmarks, especially the sulcus 
II. 
The definition of these structures (contrast between light and dark bands) 
Optical density is given greater weight. In the early stages of nuclear sclerosis, 
increased optical density is noticeable only in the normally dark bands, particularly the 
sulcus, but in advanced stages the density of all bands becomes greater. With 
increasing nuclear sclerosis, the definition of nuclear landmarks decreases, and finally 
disappears. For grading nuclear status the primary consideration is the degree of 
reflectance (sometimes termed “opalescence”) of the sulcus, with secondary 
consideration given to the definition of the nuclear features, i.e. contrast of the dark 
and bright bands. 
Nuclear Standard Photographs - Three standard photographs with increasing 
amounts of nuclear opalescence are used for grading. 
In Nuclear Standard 1 the density of the sulcus has increased so that only a suggestion 
of the sulcus can be detected. Towards the upper and lower ends of the sulcus, 
segments of what appears to be the equator of the fetal nucleus (or a zone just 
beneath its surface) are visible as steeply curved white lines. Only a small part of the 
anterior lentil is visible. The posterior nuclear surface band cannot be seen at all and 
the anterior one is very faint. 
In Nuclear Standard 2, the sulcus has become so dense that only a faint shadow marks 
its location at the centre of the lens, and the entire nucleus has become dense enough 
that lentils and lamellae are not distinguishable. 
Nuclear Standard 3 shows a further increase in nuclear density, to the point that 
neither the sulcus nor other features are distinguishable. 

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Slit Lamp Settings - Grading of nuclear opalescence is done with the illuminating beam 
of the slit lamp angled at 45° to the viewing axis, the slit beam width set at 0.3mm and 
the slit beam height set at 9mm. 
Codes for Nuclear Grading –  
I. 
None (grade 0) 
II. 
Mild (grade 1) 
III. 
Moderate (grade 2) 
IV. 
Severe (grade 3) 
Grading of Cortical Opacities 
Grading of cortical opacities is done at the slit lamp using a red reflex image. The slit 
beam height and width are set by the assessor according to their usual practice as 
long as retroillumination is obtained. The position may be changed as needed so that 
all areas of the lens can be viewed against the red reflex. With retroillumination cortical 
opacities appear darker than the adjacent red reflex. 
An area is considered involved by opacity if it is definitely more opaque than adjacent 
uninvolved areas. Opacities not seen against the red reflex are not counted. For 
comparison with the standard photographs, all areas of opacity are mentally 
rearranged into a contiguous mass and the total area of involvement is compared with 
the standard photographs. Vacuoles (small round cyst-like features) are not 
considered to be part of cortical opacity unless they are organised, e.g., part of a linear 
formation. When determining the extent of involvement, sizable clear areas bounded 
by opacity are subtracted from the total. Areas occupied by posterior cortical opacities 
that are not overlapped by anterior cortical opacities are added to obtain the total area 
of involvement. The density of opacity is not taken into account. Cortical and PSC 
opacities are differentiated from each other mainly by location, and secondarily by 
configuration. 
Cortical Standard Photographs - Cortical opacities typically are wedge-shaped and 
radially oriented, extending from the periphery toward the centre. Their appearance 
varies from dense opacity to diffuse collections of dots separated by clear areas. 
Three standards with increasing amounts of cortical opacity are used for grading 
cortical opacities. In each standard the dashed white line defines the margins of the 
opacities. 
In cortical opacity Standard 1, three small spokes project in from the periphery 
between 5 and 7 o'clock, with a clear space between the spokes at 5:00 and 5:45. 
In Standard 2, a pie-shaped wedge extends from 3 to 6 o'clock, with a separate small 
spoke at 2:30. 
Standard 3 shows a semi-circle of cortical opacity extending from 3:30 to 9:30, with a 
dense spoke projecting from it centrally, and a group of vacuoles near the 3:30 margin 
(included as opacity because they are organised). 
Codes for Cortical Grading - Grading of cortical opacities is done by comparing the 
proportion of pupillary involvement with cortical opacities in the lens to be graded and 
the proportion of involvement in the standard photographs. Only opacities seen 
against the red reflex image are counted. 
Cortical percent involvement of the entire visible lens:  
I. 
0-10% (grade 0) 
II. 
10-25% (grade 1) 
III. 
25-50% (grade 2) 
IV. 
>50% (grade 3) 

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Grading of Posterior Subcapsular Opacities: 
Grading rules are similar to those for cortical opacities except that the red reflex image 
is focused at the plane of the posterior capsule. In this position the pupillary margin 
should be blurred. PSC opacities are considered to be present only when an area is 
definitely more opaque than adjacent areas as seen against the red reflex. For 
comparison with the standard photographs, all areas of PSC opacity are mentally 
rearranged into a contiguous mass and the total area of involvement is compared with 
the standard photographs. Mittendorf dots are disregarded. The density of PSC 
opacities is not taken into account. 
PSC opacities are seen just beneath the posterior lens capsule. Frequently they are 
centred near the posterior pole of the lens. Although they usually appear as a lacy 
configuration which may contain vacuoles (any such are considered part of PSC), they 
may range from a darkly opaque network to a barely discernible diffuse haze. Because 
PSC opacities are fairly compact with few clear areas, small spaces within PSC are 
not subtracted from the estimate of extent. 
Three standard photographs with increasing amounts of PSC opacity are used for 
grading PSC opacities. In each standard the dashed white line defines the margins of 
the opacities. 
In PSC Standard Photograph 1, a roundish opacity is located just left of centre in the 
photograph. 
In PSC Standard 2 a larger opacity, also left of centre, includes vacuoles around nearly 
half of its perimeter. Within its margins of the density of the involved area is uneven, 
but the entire region is considered opacified. 
PSC Standard 3 shows a roundish opacity that is even larger and involves the centre 
of the lens. (An array of cortical spokes, located peripherally between 6:30 and 10:00 
and rather unfocused, is not considered part of PSC.) 
PSC grading is done by comparing the size of the PSC opacity in the lens to be graded 
with the size of the PSC opacity in the standard photographs. Only opacities seen 
against the red reflex image are counted. 
PSC percent pupillary involvement of the 5mm diameter central circle of the lens: 
I. 
0-2% (grade 0) 
II. 
2-20% (grade 1) 
III. 
20-50% (grade 2) 
IV. 
>50% grade 3)

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Reference Photographs taken from: [Chew 2010] 
 

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26.4. Declaration of Helsinki 
Recommendations Guiding Medical Physicians in Biomedical Research Involving 
Human Volunteers 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 
amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975 
and 
the 
35th 
World 
Medical 
Assembly, 
Venice, 
Italy, 
October 
1983 
and 
revised 
41st 
World 
Medical 
Assembly 
Hong 
Kong, 
1989 
and by the 48th World Medical Assembly, South Africa, October 1996  
Introduction 
It is the mission of the physician to safeguard the health of the people. His or her 
knowledge and conscience are dedicated to the fulfilment of this mission. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration", and the 
International Code of Medical Ethics declares that, "A physician shall act only in the 
patient's interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the patient".  
The purpose of biomedical research involving human volunteers must be to improve 
diagnostic, therapeutic and prophylactic procedures and the understanding of the 
aetiology and pathogenesis of disease. 
In current medical practice most diagnostic, therapeutic or prophylactic procedures 
involve hazards. This applies especially to biomedical research. 
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human volunteers. 
In the field of biomedical research a fundamental distinction must be recognised 
between medical research in which the aim is essentially diagnostic or therapeutic for 
a patient, and medical research, the essential object of which is purely scientific and 
without implying direct diagnostic or therapeutic value to the person volunteered to the 
research. 
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
Because it is essential that the results of laboratory experiments be applied to human 
beings to further scientific knowledge and to help suffering humanity, the World 
Medical Association has prepared the following recommendations as a guide to every 
physician in biomedical research involving human volunteers. They should be kept 
under review in the future. 
It must be stressed that the standards as drafted are only a guide to physicians all 
over the world. Physicians are not relieved from criminal, civil and ethical 
responsibilities under the laws of their own countries. 
I. Basic Principles 
Biomedical research involving human volunteers must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and 
animal experimentation and on a thorough knowledge of the scientific literature.  
The design and performance of each experimental procedure involving human 
volunteers should be clearly formulated in an experimental protocol which should be 
transmitted for consideration, comment and guidance to a specially appointed 
committee independent of the Investigator and the Sponsor provided that this 
independent committee is in conformity with the laws and regulations of the country in 
which the research experiment is performed.  

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Biomedical research on human volunteers should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human volunteer must always rest with a medically qualified 
person and never rest on the volunteer of the research, even though the volunteer has 
given his or her consent.  
Biomedical research involving human volunteers cannot legitimately be carried out 
unless the importance of the objective is in proportion to the inherent risk to the 
volunteer.  
Every biomedical research project involving human volunteers should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
volunteer or to others. Concern for the interest of the volunteer must always prevail 
over the interests of science and society.  
The right of the research volunteer to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the volunteer 
and to minimise the impact of the study on the volunteer's physical and mental integrity 
and on the personality of the volunteer.  
Physicians should abstain from engaging in research projects involving human 
volunteers unless they are satisfied that the hazards involved are believed to be 
predictable. Physicians should cease any investigation if the hazards are found to 
outweigh the potential benefits.  
In publication of the results of his or her research, the physician is obliged to preserve 
the accuracy of the results. Reports on experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication.  
In any research on human beings, each potential volunteer must be adequately 
informed of the aims, methods, anticipated benefits and potential hazards of the study 
and the discomfort it may entail. He or she should be informed that he or she is at 
liberty to abstain from participation in the study and that he or she is free to withdraw 
his or her consent to participation at any time. The physician should then obtain the 
volunteer's freely-given informed consent, preferably in writing.  
When obtaining informed consent for the research project the physician should be 
particularly cautious if the volunteer is in a dependent relationship to him or her or may 
consent under duress. In that case the informed consent should be obtained by a 
physician who is not engaged in the investigation and who is completely independent 
of this official relationship.  
In the case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the volunteer is a minor, 
permission from the responsible relative replaces that of the volunteer in accordance 
with national legislation.  
Whenever the minor child is in fact able to give consent, the minor's consent must be 
obtained in addition to the consent of the minor's legal guardian.  
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration 
are complied with.  
II. Medical Research Combined with Professional Care (CLINICAL RESEARCH) 
In the treatment of the sick person, the physician must be free to use a new diagnostic 
and therapeutic measure, if in his or her judgement it offers hope of saving life, 
re-establishing health or alleviating suffering.  
The potential benefits, hazards and discomfort of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods.  

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In any medical study, every patient - including those of a control group, if any - should 
be assured of the best proven diagnostic and therapeutic method. This does not 
exclude the use of inert placebo in studies where no proven diagnostic or therapeutic 
method exists.  
The refusal of the patient to participate in a study must never interfere with the 
physician-patient relationship.  
If the physician considers it essential not to obtain informed consent, the specific 
reasons for this proposal should be stated in the experimental protocol for 
transmission to the independent committee.  
The physician can combine medical research with professional care, the objective 
being the acquisition of new medical knowledge, only to the extent that medical 
research is justified by its potential diagnostic or therapeutic value for the patient  
III. 
Non-Therapeutic 
Biomedical 
Research 
Involving 
Human 
Volunteers 
(NON-CLINICAL BIOMEDICAL RESEARCH) 
In the purely scientific application of medical research carried out on a human being, 
it is the duty of the physician to remain the protector of the life and health of that person 
on whom biomedical research is being carried out. 
The volunteer should be volunteers - either healthy persons or patients for whom the 
experimental design is not related to the patient's illness.  
The Investigator or the investigating team should discontinue the research if in his/her 
or their judgement it may, if continued, be harmful to the individual.  
In research on man, the interest of science and society should never take precedence 
over considerations related to the well-being of the volunteer. 
 
 

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26.6. Vitreous Haze Grading Scale