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

NCT ID: NCT04566445

Last Updated: 2025-07-10

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 255 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-09-28
• Study Completion Date: 2024-06-10

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, 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.

Conditions

Dry Age-related Macular Degeneration

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

GT005 Medium dose [5E10 vg]

GT005 Medium dose \[5E10 vg\]

Group Type: EXPERIMENTAL

GT005

Intervention Type: DRUG

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.

GT005 High dose [2E11 vg]

GT005 High dose \[2E11 vg\]

Group Type: EXPERIMENTAL

GT005

Intervention Type: DRUG

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.

Untreated control

Untreated control

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Able and willing to give written informed consent

2. Age ≥55 years

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

• Minimum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: collaborator

Gyroscope Therapeutics Limited

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

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

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

Georgia Retina PC

Marietta, Georgia, United States

Illinois Retina Associates

Chicago, Illinois, United States

University Retina Macula Associates PC

Lemont, Illinois, United States

Midwest Eye Institute Northside

Indianapolis, Indiana, United States

Wolfe Eye Clinic

West Des Moines, Iowa, United States

Retina Associates, LLC

Shawnee Mission, Kansas, United States

The Retina Care Center

Baltimore, Maryland, United States

Ophthalamic Consultants of Boston (OCB)

Boston, Massachusetts, United States

Retina Associates of Michigan

Grand Blanc, Michigan, United States

Associated Retinal Consultants PC

Royal Oak, Michigan, United States

Sierra Eye Associates

Reno, Nevada, United States

Columbia University Medical Center

New York, New York, United States

Retina Associates of Western New York

Rochester, New York, United States

Duke Eye Center

Durham, North Carolina, United States

Cincinnati Eye Institute

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Retina

Eugene, Oregon, United States

Casey Eye Institute - OHSU

Portland, Oregon, United States

Erie Retinal Surgery ,INC

Erie, Pennsylvania, United States

Mid Atlantic Retina - Wills Eye Hospital

Philadelphia, Pennsylvania, United States

Palmetto Retina Center

West Columbia, South Carolina, United States

Charles Retina Institute

Germantown, Tennessee, United States

Southeastern Retina Associates, PC

Knoxville, Tennessee, United States

Austin Research Center for Retina, PLLC

Austin, Texas, United States

Retina Consultants of Houston-TMC

Bellaire, Texas, United States

Retina Foundation of the Southwest

Dallas, Texas, United States

Texas Retina Associates (Dallas)

Dallas, Texas, United States

Retinal Consultants of San Antonio

San Antonio, Texas, United States

Retina Consultants of Houston

The Woodlands, Texas, United States

Rocky Mountain Retina Consultants

Salt Lake City, Utah, United States

Department of Ophthalmology UW Medicine

Seattle, Washington, United States

Retina Center Northwest

Silverdale, Washington, United States

Sydney Hospital and Sydney Eye Hospital

Sydney, New South Wales, Australia

The University of Melbourne - The Centre for Eye Research Australia (CERA)

Melbourne E., Victoria, Australia

CHU Dijon - Hopital Mitterrand

Dijon, , France

Centre Paradis Monticelli

Marseille, , France

CHU de Nantes - Hôtel-Dieu

Nantes, , France

Universitätsklinikum Bonn

Bonn, , Germany

Internationale Innovative Ophthalmochirurgie

Düsseldorf, , Germany

Universitaetsklinikum Schleswig-Holstein - Campus Lübeck

Lübeck, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Oftalmika Spolka z ograniczona odpowiedzialnoscia

Bydgoszcz, , Poland

Instituto de microcirugía ocular

Barcelona, , Spain

Clinica Baviera

Madrid, , Spain

Clinica Universidad de Navarra - Pamplona

Pamplona, , Spain

Moorfields Eye Hospital - NHS Foundation Trust

London, , United Kingdom

Retina Clinic London

London, , United Kingdom

John Radcliffe Hospital

Oxford, , United Kingdom

Sunderland Eye Infirmary

Sunderland, , United Kingdom

Countries

United States; Australia; France; Germany; Poland; Spain; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 37314061 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

CPPY988A12201

Identifier Type: OTHER

Identifier Source: secondary_id

2020-002431-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GT005-03

Identifier Type: -

Identifier Source: org_study_id