EXPLORE: A Phase II Study to Evaluate the Safety and Efficacy of Two Doses of GT005

Phase 2

Terminated

Conditions: Dry Age-related Macular Degeneration

Interventions: Drug: GT005

Registration Number: NCT04437368

Lead Sponsor: Gyroscope Therapeutics Limited

Brief Summary: The purpose of this clinical study was to evaluate the safety and efficacy of two doses of GT005 administered as a single subretinal injection in subjects with geographic atrophy secondary to age-related macular degeneration (AMD).

Detailed Description: This was a Phase II, outcomes assessor-masked, multicentre, randomized study to assess the safety and efficacy of two doses of GT005 administered as a single-time subretinal injection in subjects with Geographic Atrophy (GA) secondary to age-related macular degeneration (AMD). Approximately 202 subjects were planned to be randomized to GT005 or the untreated control group.

Subjects entered the study had genotyping and serum complement factor I(CFI) levels assessed. Assessments were either performed at a sponsor-approved laboratory during the EXPLORE screening period or provided through participation in a previous Gyroscope sponsored study. If subjects failed to meet the eligibility criteria for EXPLORE, they were classified as screen failures for this study and could be considered for entry into another Novartis/Gyroscope sponsored study.

After providing the informed consent, subjects underwent ophthalmic and clinical assessments to determine eligibility for inclusion in the study.

Upon confirmation of eligibility, subjects in part 1 were randomized to one of two groups: low dose \[2E10 vg\], or high dose \[2E11 vg\]. Within each group, subjects were allocated to GT005 or untreated control based on a 2:1 ratio. Once part 1 enrolment was completed, and the last active subject completed screening and either was screen-failed or randomized, then Part 2 could commence. In part 2, subjects were randomized to the low dose \[2E10\] group or untreated control based on a 2:1 ratio. The study eye was identified for all subjects.

Subjects were stratified by GA lesion size on fundus autofluorescence (FAF) (≤10 mm2 or \>10 mm2) and presence of choroidal neovascularisation (CNV) in the fellow eye (Yes or No). Randomization of study eyes in the GA lesion size upper stratum of \>10 mm2 to 17.5 mm2 was capped at 20% of total subjects randomized. Once enrolment capping at 20% based on the upper GA lesion size was reached, eyes that fulfilled the cap criteria were no longer eligible, unless the subject had a CFI rare variant genotype (minor allele frequency ≤1%) previously associated with normal or low serum CFI or had an unreported CFI rare variant genotype. Of all subjects enrolled and randomized in the study, the presence of CNV in the fellow eye was capped at 25% per stratum. A permuted-block randomization method was used to obtain an approximately 2:1 ratio between GT005 and the untreated control groups for each dose group within each stratum.

Following randomization, the investigator was informed of the subject's allocated treatment (GT005 or the untreated control group) and the study eye selected. To minimize bias, all imaging endpoint assessments and grading were performed at a Central Reading Centre (CRC), in a masked fashion. For part 1, the Sponsor, subject, investigators, and study personnel performing clinical assessments remained masked to dose received for those allocated to GT005. For part 2, the Sponsor, investigators, subjects, and study personnel performing clinical assessments were unmasked to dose received, since only the low dose was administered.

Subjects randomized to GT005 underwent a single time subretinal administration of the study drug. Vitreous samples were collected during surgery. Following surgery, a prophylactic steroid regimen was prescribed.

The study consisted of a screening period lasting up to 8 weeks (or up to 12 weeks if agreed by the Sponsor Medical Monitor), followed by a 96-week study period. All subjects were assessed for the occurrence of adverse events (AEs) at each visit and underwent functional visual and retinal imaging,anatomical assessments, and biological sampling as per the schedule of assessments.

This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review board (IRBs), informed consent regulations, the Declaration of Helsinki, International Council on Harmonisation (ICH) Good Clinical Practices (GCP) Guidelines, and the Food and Drug Administration (FDA) guidance.

On 24-Aug-2023, the decision was taken to terminate the study and the GT005 program. The decision was aligned with the recommendation of an independent DMC, which concluded that futility criteria had been met for the HORIZON study (GT005-03) and the overall benefit-risk ratio did not support continuation of the current development program as planned. All GT005- treated subjects, who were willing to be transferred into the long-term safety follow-up study were enrolled in the ORACLE (CPPY988A12203B / NCT05481827) study.

In both Part 1 and Part 2, patients with geographic atrophy secondary to age-related macular degeneration were enrolled. In Part 1, patients with CFI rare variant genotype and low serum CFI level and in Part 2, patients were enrolled regardless of genotypes. Efficacy results were analyzed by arm and also by part. AE and disposition data were reported per arm, but the parts were combined, according to the analysis plan.

Part 1 enrolled subjects with CFI rare variant; Part 2 enrolled subjects regardless of genotype.

There were no subjects in the high dose arm in Part 2.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 98

Inclusion Criteria

Able and willing to give written informed consent
Age ≥55 years
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)
Have GA lesion(s) total size between or equal to 1.25mm2 to 17.5mm2 in the study eye
The GA lesion(s) in the study eye must reside completely within the FAF image
Up to 25% of the enrolled study population are permitted to have CNV in the fellow eye, defined as either:
1. Non-exudative/sub-clinical fellow eye CNV identified at Screening, or
2. Known history of fellow eye CNV with either ≥2 years since diagnosis or with no active treatment required in 6 months prior to Screening
Have a BCVA of 24 letters (6/95 and 20/320 Snellen acuity equivalent) or better, using ETDRS charts, in the study eye
Part 1 Only: 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
Able to attend all study visits and complete the study procedures
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

Subjects who have a clinical diagnosis of Stargardt Disease or other retinal dystrophies, confirmed by the central reading centre
Have a history, or evidence, of CNV in the study eye
Presence of moderate/severe or worse non-proliferative diabetic retinopathy in the study eye
Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study eye
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
Have clinically significant cataract that may require surgery during the study period in the study eye
Presence of moderate to severe glaucomatous optic neuropathy in the study eye; uncontrolled IOP despite the use of two or more topical agents; a history of glaucoma-filtering or valve surgery is also excluded
Axial myopia of greater than -8 dioptres in the study eye
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
Have a contraindication to specified protocol corticosteroid regimen
Have received any investigational and/or approved product(s) 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 in the study eye or systemically
Have received a gene or cell therapy at any time
Are unwilling to use two forms of contraception (one of which being a barrier method) for 90 days post-dosing, if relevant
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GT005 Low dose [2E10 vg]	GT005	GT005 Low dose \[2E10 vg\] (Parts 1 and 2)
GT005 High dose [2E11 vg]	GT005	GT005 High dose \[2E11 vg\] (Part 1)

Primary Outcome Measures

Name	Time	Method
The Change From Baseline to Week 48 in Geographic Atrophy (GA) - Part 1	Baseline, Weeks 12, 24, 36, and 48	The change from baseline to Week 48 in GA area as measured by fundus autofluorescence (FAF)

Secondary Outcome Measures

Name	Time	Method
The Change From Baseline in Geographic Atrophy (GA) at Week 72 and Week 96 - Part 1	Baseline, Weeks 72 and 96	The change from baseline to Week 48 in GA area as measured by fundus autofluorescence (FAF)
Summary of Adverse Events - Parts 1 and 2 Combined	Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs.
Ocular Adverse Events by Primary System Organ Class and Preferred Term for the Study Eye - Parts 1 and 2 Combined	Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs. System organ classes are sorted alphabetically, and preferred terms are sorted by decreasing overall frequency within system organ class.
Non-ocular Adverse Events - Summary - Parts 1 and 2 Combined	Adverse events are reported from randomization up to end of study, for a maximum timeframe of approximately 96 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject. A TEAE is defined as any AE that develops after randomization or any AE already present that worsens following randomization. The primary summaries of AEs are based on TEAEs.
Change in GA Morphology From Baseline to Week 96 on Colour Fundus Photography (CFP) - Number of Participants With Increase in Fundus Autofluorescence (FAF) - Part 1	Baseline, Weeks 5,12,24,36,48,72,96	Change in GA morphology on multimodal imaging through Week 96. FAF images at Week 5 were introduced via a protocol amendment after most participants had already completed Week 5; therefore, only a minimal number of patients had FAF images taken at Week 5 for Part 1.
Change From Baseline to Week 48 in GA Morphology on Colour Fundus Photography (CFP) - Number of Participants With Increase in Fundus Autofluorescence - Part 2	Baseline, Weeks 5,12,24,36,48	Change in GA morphology on multimodal imaging through Week 48. For the untreated control group, there were no protocol-specified visits for Weeks 5 and 8. The untreated control participants were immediately discontinued from the study when the study was early terminated; therefore Week 36 and 48 data in part 2 were not applicable for these the untreated control group.
Change in Best Corrected Visual Acuity (BCVA) Score From Baseline Through Week 96 Via the Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 1	Baseline, Weeks 1, 5, 8, 12, 24, 36, 48, 72 and 96	BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. For the untreated control group, there were no protocol-specified visits for Weeks 1, 5 and 8.
Change in Low Luminance Difference (LLD) Letter Count From Baseline at Weeks 12, 24, 36, 48, 72 and 96, Via Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 1	Baseline, Weeks 12, 24, 36, 48, 72 and 96	LLD was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. The test was to be performed after BCVA testing, prior to pupil dilation, and distance refraction was to be carried out before Low Luminance Visual Acuity (LLVA) was measured. LLVA was to be measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. The LLD was calculated as the difference between BCVA and LLVA. Initially, letters were to be read at a distance of 4 metres from the chart. If \<20 letters were read at 4 metres, testing at 1 metre should have been performed. LLD was to be reported as number of letters read correctly by the subject. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
Change in Low Luminance Difference (LLD) Letter Count From Baseline at Weeks 12, 24, 36, and 48, Via Early Treatment for Diabetic Retinopathy (ETDRS) Chart - Part 2	Baseline, Weeks 12, 24, 36, and 48	LLD was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. The test was to be performed after BCVA testing, prior to pupil dilation, and distance refraction was to be carried out before Low Luminance Visual Acuity (LLVA) was measured. LLVA was to be measured by placing a 2.0-log-unit neutral density filter over the front of each eye and having the subject read the normally illuminated ETDRS chart. The LLD was calculated as the difference between BCVA and LLVA. Initially, letters were to be read at a distance of 4 metres from the chart. If \<20 letters were read at 4 metres, testing at 1 metre should have been performed. LLD was to be reported as number of letters read correctly by the subject. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Reading Performance, Measured as the Maximum Reading Speed (Words Per Minute), as Assessed by Minnesota Low-vision Reading Test (MNRead) Chart - Part 1	Baseline, Weeks 24, 36, 48, 72 and 96	The maximum reading speed (MRS) represents the highest reading speed an individual can achieve when print size is not a limiting factor. Essentially, it measures how quickly a person can read text when the print is large enough to be easily readable. A higher count represents better visual functioning.
Change From Baseline at Weeks 24, 36 and 48 in Reading Performance, Measured as the Maximum Reading Speed (Words Per Minute), as Assessed by Minnesota Low-vision Reading Test (MNRead) Chart - Part 2	Baseline, Weeks 24, 36 and 48	A higher count represents better visual functioning. The untreated control participants were immediately discontinued from the study when the study was early terminated; therefore Week 36 and 48 data in part 2 were not applicable for these the untreated control group.
Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Functional Reading Independence (FRI) Index - Part 1	Baseline, Weeks 24, 36, 48, 72 and 96	The FRI index is a patient-reported outcome measure developed specifically for use in GA patients. The FRI index evaluates the level of independence subjects have in performing everyday activities that require reading, such as writing a cheque or reading a prescription. Scores derived from the index range from 1 (unable to do) to 4 (total independence). A higher score represents better visual functioning.
Change From Baseline at Weeks 24, 36 and 48 in Functional Reading Independence (FRI) Index - Part 2	Baseline, Weeks 24, 36 and 48	The FRI index is a patient-reported outcome measure developed specifically for use in GA patients. The FRI index evaluates the level of independence subjects have in performing everyday activities that require reading, such as writing a cheque or reading a prescription. Scores derived from the index range from 1 (unable to do) to 4 (total independence). A higher score represents better visual functioning. The untreated control participants were immediately discontinued from the study when the study was early terminated; therefore Week 36 and 48 data in part 2 were not applicable for these the untreated control group.
Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Patient Reported Outcomes (Visual Function Questionnaire-25) - Composite Score - Part 1	Baseline, Weeks 24, 36, 48, 72 and 96	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. A composite score is derived based on the average of the 11 subscales.
Change From Baseline at Weeks 24, 36 and 48 in Patient Reported Outcomes (Visual Function Questionnaire-25) - Composite Score - Part 2	Baseline, Weeks 24, 36, and 48	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. A composite score is derived based on the average of the 11 subscales. The untreated control participants were immediately discontinued from the study when the study was early terminated; therefore Week 36 and 48 data in part 2 were not applicable for these the untreated control group.

Trial Locations

Locations (55): Retinal Research Institute (retina consultants of AZ)
🇺🇸
Phoenix, Arizona, United States
Retina Associates of Southern California
🇺🇸
Huntington Beach, California, United States
Byers Eye Institute at Stanford
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Palo Alto, California, United States
Retina Consultants San Diego
🇺🇸
Poway, California, United States
VitreoRetinal Associates, P.A.
🇺🇸
Gainesville, Florida, United States
Bascom Palmer Eye Institute
🇺🇸
Miami, Florida, United States
Retina Vitreous Associates of Florida
🇺🇸
St. Petersburg, Florida, United States
Southeast Retina Center
🇺🇸
Augusta, Georgia, United States
University Retina Macula Associates PC
🇺🇸
Lemont, Illinois, United States
Midwest Eye Institute Northside
🇺🇸
Indianapolis, Indiana, United States
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Retinal Research Institute (retina consultants of AZ)
🇺🇸Phoenix, Arizona, United States