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

HORIZON: A Phase II, Open-label, 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 Geographic Atrophy Secondary to Dry Age-related Macular Degeneration

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).

Study Overview

• Status: Terminated
• Conditions: Dry Age-related Macular Degeneration
• Intervention / Treatment: Drug: GT005

Detailed Description

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
• Enrollment (Actual): 255
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2000
      • Sydney Hospital and Sydney Eye Hospital
  • Victoria
    • Melbourne E., Victoria, Australia, 3002
      • The University of Melbourne - The Centre for Eye Research Australia (CERA)
• France
  • Dijon, France, 21000
    • CHU Dijon - Hopital Mitterrand
  • Marseille, France, 13008
    • Centre Paradis Monticelli
  • Nantes, France, 44093
    • CHU de Nantes - Hotel-Dieu
• Germany
  • Bonn, Germany, 53127
    • Universitatsklinikum Bonn
  • Düsseldorf, Germany, 40549
    • Internationale Innovative Ophthalmochirurgie
  • Lübeck, Germany, 23562
    • Universitaetsklinikum Schleswig-Holstein - Campus Lübeck
  • Tübingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
• Poland
  • Bydgoszcz, Poland, 85-631
    • Oftalmika Spolka z ograniczona odpowiedzialnoscia
• Spain
  • Barcelona, Spain, 08035
    • Instituto de Microcirugia Ocular
  • Madrid, Spain, 28046
    • Clinica Baviera
  • Pamplona, Spain, 31008
    • Clinica Universidad de Navarra - Pamplona
• United Kingdom
  • London, United Kingdom, W1G 7LB
    • Retina Clinic London
  • London, United Kingdom, EC1V 2PD
    • Moorfields Eye Hospital - NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • Sunderland, United Kingdom, SR2 9HP
    • Sunderland Eye Infirmary
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85053
      • Retinal Research Institute (retina consultants of AZ)
  • California
    • Beverly Hills, California, United States, 90211
      • Retina Vitreous Associates Medical Group
    • Fullerton, California, United States, 92835
      • Retina Consultants of Orange County
    • Mountain View, California, United States, 94040
      • Northern California Retina Vitreous Associates
    • Palo Alto, California, United States, 94303
      • Byers Eye Institute at Stanford
    • Poway, California, United States, 92064
      • Retina Consultants of San Diego
    • Sacramento, California, United States, 95817
      • University of California (UC) Davis Medical Group Eye Center
  • Colorado
    • Durango, Colorado, United States, 81303
      • Southwest Retina Research Center
  • Florida
    • Deerfield Beach, Florida, United States, 33064
      • Rand Eye Institute
    • Gainesville, Florida, United States, 32607
      • VitreoRetinal Associates, P.A.
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
    • St. Petersburg, Florida, United States, 33711
      • Retina Vitreous Associates of Florida
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center
    • Marietta, Georgia, United States, 30060
      • Georgia Retina PC
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Illinois Retina Associates
    • Lemont, Illinois, United States, 60452
      • University Retina Macula Associates PC
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Midwest Eye Institute Northside
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Wolfe Eye Clinic
  • Kansas
    • Shawnee Mission, Kansas, United States, 66204
      • Retina Associates, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21209
      • The Retina Care Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Ophthalamic Consultants of Boston (OCB)
  • Michigan
    • Grand Blanc, Michigan, United States, 48439
      • Retina Associates of Michigan
    • Royal Oak, Michigan, United States, 48073
      • Associated Retinal Consultants PC
  • Nevada
    • Reno, Nevada, United States, 89502
      • Sierra Eye Associates
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14620
      • Retina Associates of Western New York
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Eye Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Cincinnati Eye Institute
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Oregon Retina
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute - OHSU
  • Pennsylvania
    • Erie, Pennsylvania, United States, 16507
      • Erie Retinal Surgery ,INC
    • Philadelphia, Pennsylvania, United States, 19107
      • Mid Atlantic Retina - Wills Eye Hospital
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Palmetto Retina Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Charles Retina Institute
    • Knoxville, Tennessee, United States, 37922
      • Southeastern Retina Associates, PC
  • Texas
    • Austin, Texas, United States, 78705
      • Austin Research Center for Retina, PLLC
    • Bellaire, Texas, United States, 77401
      • Retina Consultants of Houston-TMC
    • Dallas, Texas, United States, 75231
      • Retina Foundation of the Southwest
    • Dallas, Texas, United States, 75231
      • Texas Retina Associates (Dallas)
    • San Antonio, Texas, United States, 78240
      • Retinal Consultants of San Antonio
    • The Woodlands, Texas, United States, 77384
      • Retina Consultants of Houston
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Rocky Mountain Retina Consultants
  • Washington
    • Seattle, Washington, United States, 98104-2499
      • Department of Ophthalmology UW Medicine
    • Silverdale, Washington, United States, 98383
      • Retina Center Northwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 51 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able and willing to give written informed consent
2. Age ≥55 years
3. a. In Stage 1: 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; b. In Stage 2: Have a clinical diagnosis of GA secondary to AMD in the study eye, as determined by the Investigator, that is non-foveal, as determined by the central reading centre, or has a CFI rare variant genotype and meets inclusion criteria 3a, and a diagnosis of AMD in the contralateral eye (except if monocular)
4. GA lesion(s) within an acceptable size on FAF, 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
7. Have a BCVA of ≥24 letters (6/95 or 20/320 Snellen acuity equivalent), using ETDRS charts, in the study eye
8. a. In Stage 1: Meet one of the pre-specified AMD genetic subgroup criteria; b. In Stage 2: Genotyping is not required for study eligibility
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 (not required for postmenopausal women) or provide documentation of being surgically sterilised

Exclusion Criteria:

1. a. In Stage 1: Carriers of excluded genetic variants; b. In Stage 2: Subjects are excluded if they have a clinical diagnosis of Stargardt Disease or other retinal dystrophies
2. Have a history, or evidence, of CNV in the study eye
3. Presence of moderate/severe or worse non-proliferative, diabetic retinopathy in the study eye
4. Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study eye
5. History of intraocular surgery in the study eye within 12 weeks prior to Visit 1
6. Have clinically significant cataract that may require surgery during the study period in the study eye
7. Presence of moderate to severe glaucomatous optic neuropathy, uncontrolled intraocular pressure (IOP), despite use of two or more topical agents; or a history of glaucoma-filtering or valve surgery
8. Axial myopia of greater than -8 diopters in the study eye
9. 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
10. Have received a gene or cell therapy at any time.
11. Have a contraindication to the protocol specified corticosteroid regimen
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
14. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Untreated control
Experimental: GT005 Medium dose [5E10 vg]	Drug: GT005; 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.
Experimental: GT005 High dose [2E11 vg]	Drug: GT005; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change From Baseline to Week 72 in Geographic Atrophy (GA)	GA area as measured by fundus autofluorescence (FAF)	Baseline, Weeks 12, 24, 36, 48 and 72

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Change From Baseline at Week 96 in Geographic Atrophy (GA)	GA area as measured by fundus autofluorescence (FAF)	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.	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.	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.	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.	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.	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.	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.	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.	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.	Baseline, Weeks 24, 36, 48, 72 and 96

Collaborators and Investigators

• Sponsor: Gyroscope Therapeutics Limited
• Collaborators: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Tzoumas N, Riding G, Williams MA, Steel DH. Complement inhibitors for age-related macular degeneration. Cochrane Database Syst Rev. 2023 Jun 14;6(6):CD009300. doi: 10.1002/14651858.CD009300.pub3.

Helpful Links

• Novartis Clinical Trial Results

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Actual): June 10, 2024
• Study Completion (Actual): June 10, 2024

Study Registration Dates

• First Submitted: September 9, 2020
• First Submitted That Met QC Criteria: September 22, 2020
• First Posted (Actual): September 28, 2020

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 8, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Retinal disease; Eye disease; Retinal degeneration; Macular atrophy; Dry age-related macular degeneration; Geographic atrophy
• Additional Relevant MeSH Terms: Connective Tissue Diseases; Skin Diseases; Eye Diseases, Hereditary; Skin Abnormalities; Macular Degeneration; Skin and Connective Tissue Diseases; Retinal Diseases; Eye Diseases; Retinal Degeneration; Geographic Atrophy; Anetoderma
• Other Study ID Numbers: GT005-03; CPPY988A12201 (Other Identifier: Novartis); 2020-002431-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No