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).
This was a Phase II, open-label, outcomes-assessor masked, multicenter, randomized, controlled study designed to evaluate 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 250 subjects, across Stage 1 and Stage 2, were planned to be randomized to one of two doses of GT005 or the untreated control group. Subjects entered the study had genotyping and serum Complement factor I (CFI) levels assessed either through participation in a previous Gyroscope sponsored study, or a Sponsor-approved laboratory during the HORIZON screening period. If both eyes are eligible; the eye with the worse visual acuity will be selected as the study eye. If subjects failed to meet the eligibility criteria for this study, they were classified as screen failures and could be considered for entry into another Novartis/Gyroscope sponsored study. After providing the informed consent, subjects underwent ophthalmic and clinical assessments to determined eligibility for inclusion in the study. Upon confirmation of eligibility, subjects were randomized to one of two dose groups (medium dose \[5E10 vg\] or high dose \[2E11 vg\]). Within each dose group, subjects were allocated to GT005, or untreated control based on a 2:1 ratio. The overall study population (N=approximately 250) aimed to include approximately 60% of subjects with foveal GA and 40% of subjects with non-foveal GA (extrafoveal lesions). The study eye was identified for all subjects. Enrolment for HORIZON were composed of two stages. Stage 1 enrolled subjects with foveal or non-foveal GA until 180 subjects were randomized. Stage 2 enrolled subjects with nonfoveal GA. Subjects with a CFI rare variant associated with normal or low serum CFI were also allowed to be enrolled in Stage 2, irrespective of GA foveal involvement. Subjects were stratified by GA lesion size on Fundus autofluorescence (FAF) (≤10 mm2 or \>10 mm2) and AMD genotype subgroup. 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 in Stage 1 and Stage 2, respectively. In Stage 2, once enrolment capping at 20% based on 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 (Group 1 and 5). A permuted-block 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 during imaging grading, all imaging endpoint assessments and grading were performed at a Central reading centre (CRC). All imaging efficacy assessments were performed in a masked fashion. The Sponsor, subjects, investigators, and study personnel performing clinical assessments remained masked to the dose received for those allocated to GT005. For each subject, the study comprised 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 AEs at each visit and underwent functional assessments, retinal imaging, and biological sampling as per the schedule of assessments. This study was conducted in compliance with Independent ethics committees (IECs) / Institutional review boards (IRBs), informed consent regulations, the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and the Food and Drug Administration (FDA), 21 Code of Federal Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for Industry: Computerised Systems Used in Clinical Trials. 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 Data monitoring committee (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) study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
255
GT005 is a recombinant, non-replicating AAV2 expressing human complement factor I (CFI). GT005 was administered as a single time subretinal injection into the study eye of subjects allocated to one of the two GT005 doses.
The Change From Baseline to Week 72 in Geographic Atrophy (GA)
GA area as measured by fundus autofluorescence (FAF)
Time frame: Baseline, Weeks 12, 24, 36, 48 and 72
The Change From Baseline at Week 96 in Geographic Atrophy (GA)
GA area as measured by fundus autofluorescence (FAF)
Time frame: Baseline, Week 96
Summary of Adverse Events
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.
Time frame: Adverse events are reported from randomization to the end of study, at Week 96, up to a maximum timeframe of approximately 96 weeks.
Ocular AEs Occurring in ≥2% of Subjects by Primary System Organ Class and Preferred Term for the Study Eye
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.
Time frame: Adverse events are reported from randomization to the end of study, at Week 96, up to a maximum timeframe of approximately 96 weeks.
Non-ocular AEs Occurring in ≥2% of Subjects
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.
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Retinal Research Institute (retina consultants of AZ)
Phoenix, Arizona, United States
Retina Vitreous Associates Medical Group
Beverly Hills, California, United States
Retina Consultants of Orange County
Fullerton, California, United States
Northern California Retina Vitreous Associates
Mountain View, California, United States
Byers Eye Institute at Stanford
Palo Alto, California, United States
Retina Consultants of San Diego
Poway, California, United States
University of California (UC) Davis Medical Group Eye Center
Sacramento, California, United States
Southwest Retina Research Center
Durango, Colorado, United States
Rand Eye Institute
Deerfield Beach, Florida, United States
VitreoRetinal Associates, P.A.
Gainesville, Florida, United States
...and 52 more locations
Time frame: Adverse events are reported from randomization to the end of study, at Week 96, up to a maximum timeframe of approximately 96 weeks.
Change in GA Morphology From Baseline to Week 96 on Multimodal Imaging - Number of Participants With Increase in Fundus Autofluorescence
Change in retinal morphology on multimodal imaging. For the untreated control group, there were no protocol-specified visits at Week 5.
Time frame: Baseline, Weeks 5, 12, 24, 36, 48, 72 and 96
Change in Best Corrected Visual Acuity (BCVA) Score From Baseline Through Week 96 Via the Early Treatment for Diabetic Retinopathy (ETDRS) Chart
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.
Time frame: Baseline, Weeks 1, 5, 8, 12, 24, 36, 48, 72 and 96
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
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.
Time frame: Baseline, Weeks 12, 24, 36, 48, 72 and 96
Reading Performance, Measured as the MRS (Words Per Minute), as Assessed by Minnesota Low-vision Reading Test (MNRead) Chart: Summary Statistics for Change From Baseline by Visit for the Study Eye
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.
Time frame: Baseline, Weeks 12, 24, 36, 48, 72 and 96
Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Functional Reading Independence (FRI) Index
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.
Time frame: Baseline, Weeks 24, 36, 48, 72 and 96
Change From Baseline at Weeks 24, 36, 48, 72 and 96 in Patient Reported Outcomes (Visual Function Questionnaire-25) - Composite Score
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.
Time frame: Baseline, Weeks 24, 36, 48, 72 and 96