The overall objectives of the study are to evaluate the safety and efficacy (anatomical and functional visual outcomes) of two doses of GT005 in genetically defined subjects with GA due to AMD.
ID
Source
Brief title
Condition
- Vision disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
• The change in GA area from baseline to Week 48 measured by fundus
autofluorescence (FAF)
Secondary outcome
Secondary endpoints:
• The change from baseline to Week 72 and Week 96 in GA areas as measured
by fundus Autofluorescence (FAF)
• Frequency of Treatment Emergent Adverse Events (AEs)
• Change on ophthalmic examination.
• Change in other parameters of safety, including imaging modalities, Best
Corrected Visual Acuity (BCVA), vital signs, and laboratory assessments
• Change in retinal microstructures on optical coherence tomography (OCT)
• Change in presence of area of nascent GA on OCT
• Change in GA morphology on multimodal imaging
• Macular Sensitivity as assessed by Mesopic Microperimetry
• Change in BCVA Score via the early treatment for diabetic retinopathy (ETDRS)
chart
• Change in Low Luminance Difference (LLD) via the ETDRS chart
• Change in reading performance as assessed by Minnesota Low-Vision Reading
Test (MNRead) Chart
• Change in Functional Reading Independence (FRI Index)
• Change in quality of life measured on the Visual Functioning Questionnaire-25
(VFQ-25)
Exploratory endpoints:
• Change in local and systemic levels of proteins including complement proteins
and protein biomarkers associated with AMD
• Antibody titre to AAV2 and CFI, and T-cell response to AAV2 in GT005 treated
subjects
Background summary
Dry AMD is a disease of the retina that results in loss of vision in the macula
(center of the eye). When Dry AMD progresses, this can lead to a condition
called Geographic Atrophy (GA) causing further loss of vision due to
degeneration of the cells in the retina. Eventually, this may lead to blurred
or loss of bision that affects one or both eyes.
There is currently no treatment available for Dry AMD.
A family history of Dry AMD increases the risk of developing the disease, which
suggests there is a genetic link. It has also been shown that over-activation
of a part of the immune system called the complement system further contributes
to the disease.
A recent study has shown that subjects with a known family history risk who
have an over-active complement system are at an even higher risk of developing
severe Dry AMD disease than subjects that do not have these two risk factors.
AAV2 vector-based CFI gene transfer (GT005) is expected to provide a sustained
expression of human CFI in AMD patients* eyes, which would result in
down-regulation of the alternative complement pathway.
Study objective
The overall objectives of the study are to evaluate the safety and efficacy
(anatomical and functional visual outcomes) of two doses of GT005 in
genetically defined subjects with GA due to AMD.
Study design
This is a Phase 2, outcomes assessor-masked, multicentre, randomised ,
controlled study to evaluate the safety and efficacy of two doses of GT005
administered as a single subretinal injection in subjects with GA secondary to
AMD. Approximately 75 subjects are planned to be randomised to GT005 or the
untreated control group.
Intervention
The study will test two doses of GT005; low dose (2E10 vg) and high dose (2E11
vg). These doses are selected to optimise the ability to demonstrate a
therapeutic effect and identify minimal effective dose.
Subjects allocated to treatment are injected with GT005 in a three-step
procedure. First a pars plana vitrectomy is performed and then the retina is
partially detached through a cannula using balanced salt solution in order to
form a bleb. Once the bleb is formed, a fixed volume (100 µL) of the allocated
dose of GT005 is injected into the subretinal space that has been created.
Study burden and risks
Potential Benefit:
AMD is a progressive degenerative disease and is the most common cause of
blindness among the elderly in the western world. Supplementing AMD subjects
with human CFI (a down regulator of the complement system) has the potential to
dampen an over-activated complement system associated with AMD and slow down
disease progression. Using AAV2 vector based CFI gene transfer (GT005) is a way
to ensure sustained expression of human CFI in subjects* eyes with one single
injection. The true impact of GT005 can only be hypothesised as participants
may not receive any clinical benefit. Given the degenerative nature of AMD, it
is not expected to see any gain in visual acuity as once RPE and photoreceptors
have degenerated, the function is definitively lost in the atrophic area. The
potential benefit would be to slow down macular atrophy extension and
ultimately prevent future visual loss.
Risk/Benefit:
GT005 is currently being evaluated in an ongoing Phase 1/2 clinical study and
therefore the potential risks are based on clinical data from an ongoing dose
escalation safety study, preclinical data, and available scientific knowledge
of AAV2 vectors carrying different transgenes for the treatment of various
retinal conditions without significant AEs related to these Drug Products.
The main product-related risks are the generation of cellular and/or humoral
immune responses to the AAV capsid. ATA 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 technique for the subretinal delivery of gene therapy builds upon
established subretinal procedures such as subretinal tissue plasminogen
activator injection and has been further developed and successfully used for
the Choroidemia gene therapy clinical studies.
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.
Rolling Stock Yard 118 York Way
London N7 9AS
GB
Rolling Stock Yard 118 York Way
London N7 9AS
GB
Listed location countries
Age
Inclusion criteria
1. Able and willing to give written informed consent
2. Age >=55 years
3. 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)
4. Have GA lesion(s) total size between or equal to 1.25mm2 to 17.5mm2 in the
study eye
5. The GA lesion in the study eye must reside completely within the FAF image
6. Up to 25% of the enrolled study population 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
7. Have a BCVA of 24 letters (6/95 and 20/320 Snellen acuity equivalent) or
better, using ETDRS charts, in the study eye
8. Subjects carrying a CFI rare variant genotype (minor allele frequency of <=
1%) previously associated with low serum CFI or subjects carrying
an unreported CFI rare variant genotype that have tested to have a low
serum CFI
9. Able to attend all study visits and complete the study procedures
10. Women of child-bearing potential must have a negative pregnancy test within
2 weeks prior to randomisation. 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 a history, or evidence, of CNV in study eye
2. Presence of moderate/severe or worse non-proliferative diabetic retinopathy
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). Yttrium aluminium garnet capsulotomy is
permitted if performed >10 weeks prior to 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 intraocular pressure (IOP), despite the use of
more than two topical agents, a history of glaucoma-filtering or valve
surgery
7. Axial myopia of greater than -8 dioptres in the study eye
8. 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
9. Have a contraindication to the specified protocol corticosteroid regimen
10. 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
11. Have received a gene or cell therapy at any time
12. Are unwilling to use two forms of contraception (one of which being a
barrier method) for 90 days post-dosing, if relevant
13. 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003421-22-NL |
| CCMO | NL71665.000.19 |