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

NCT ID: NCT04437368

Last Updated: 2025-09-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 98 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-26
• Study Completion Date: 2024-04-05

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.

Conditions

Dry Age-related Macular Degeneration

Study Design

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

Study Groups

GT005 Low dose [2E10 vg]

GT005 Low dose \[2E10 vg\] (Parts 1 and 2)

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 \[2E11 vg\] (Part 1)

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 (Parts 1 and 2)

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

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(s) 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:

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

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. 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

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. Subjects who have a clinical diagnosis of Stargardt Disease or other retinal dystrophies, confirmed by the central reading centre

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 Screening (Visit 1). Yttrium aluminium garnet capsulotomy is permitted if performed >10 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 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

8. Axial myopia of greater than -8 dioptres in the study eye

9. 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

10. Have a contraindication to specified protocol corticosteroid regimen

11. 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

12. Have received a gene or cell therapy at any time

13. Are unwilling to use two forms of contraception (one of which being a barrier method) for 90 days post-dosing, if relevant

14. 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

• 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 Associates of Southern California

Huntington Beach, California, United States

Byers Eye Institute at Stanford

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

Wolfe Eye Clinic

West Des Moines, Iowa, United States

The Retina Care Center

Baltimore, Maryland, United States

Ophthalmic Consultants of Boston (OCB)

Boston, Massachusetts, United States

VitreoRetinal Surgery, PLLC

Minneapolis, Minnesota, United States

Sierra Eye Associates

Reno, Nevada, United States

Vision Research Center Eye Associates of New Mexico

Albuquerque, New Mexico, United States

Columbia University Medical Center

New York, New York, United States

Retina Associates of Western New York

Rochester, New York, United States

Cincinnati Eye Institute

Cincinnati, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

Oregon Retina

Eugene, Oregon, United States

Casey Eye Institute

Portland, Oregon, United States

Erie Retinal Surgery, INC

Erie, Pennsylvania, United States

Mid Atlantic Retina

Philadelphia, Pennsylvania, United States

Southeastern Retina Associates, PC

Knoxville, Tennessee, United States

Charles Retina Institute

Memphis, Tennessee, United States

Austin Research Center for Retina, PLLC

Austin, Texas, United States

Retina Consultants of Houston-TMC

Bellaire, Texas, United States

Texas Retina Associates

Dallas, Texas, United States

Retinal Consultants of San Antonio

San Antonio, Texas, United States

Department of Ophthalmology UW Medicine

Seattle, Washington, United States

West Virginia University

Morgantown, West Virginia, United States

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

Melbourne E., Victoria, Australia

Sydney Hospital and Sydney Eye Hospital

Sydney, , Australia

Centre Paradis Monticelli

Marseille, Alpes-Cote d'Azur, France

CHU Hôpital F. Mitterrand

Dijon, Bourgogne-Franche-Comté, France

CHU de Nantes - Hôtel-Dieu

Nantes, Pays de la Loire Region, France

Universitaetsklinikum Schleswig-Holstein Campus Lübeck

Lübeck, Schleswig-Holstein, Germany

Universitaetsklinikum Bonn

Bonn, , Germany

Internationale Innovative Ophthalmochirurgie

Düsseldorf, , Germany

St. Franziskus-Hospital

Münster, , Germany

Universitatsklinikum Tübingen

Tübingen, , Germany

Stichting Radboud Universitair Medisch Centrum

Nijmegen, , Netherlands

Oftalmika Spolka z ograniczona odpowiedzialnoscia

Bydgoszcz, , Poland

Hospital Universitari General de Catalunya

Sant Cugat del Vallès, Barcelona, Spain

Clinica Universidad de Navarra - Pamplona

Pamplona, Navarre, Spain

Hospital La Arruzafa

Córdoba, , Spain

Clinica Baviera

Madrid, , Spain

Clinica Oftalvist Valencia

Valencia, , Spain

Bristol Eye Hospital

Bristol, , United Kingdom

St.Paul's Eye Unit

Liverpool, , United Kingdom

Moorfields Eye Hospital - NHS Foundation Trust

London, , United Kingdom

The Retina Clinic London

London, , United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, , United Kingdom

Sunderland Eye Infirmary

Sunderland, , United Kingdom

Countries

United States; Australia; France; Germany; Netherlands; 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

CPPY988A12202

Identifier Type: OTHER

Identifier Source: secondary_id

2019-003421-22

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GT005-02

Identifier Type: -

Identifier Source: org_study_id