FOCUS: A Phase I/II First in Human Study to Evaluate the Safety and Efficacy of GT005 Administered in Subjects With Dry AMD

Phase 1

Terminated

Conditions: Macular Degeneration
Retinal Degeneration
Dry Age-related Macular Degeneration
Eye Diseases
Macular Atrophy
Retinal Disease
Geographic Atrophy

Interventions: Biological: GT005

Registration Number: NCT03846193

Lead Sponsor: Gyroscope Therapeutics Limited

Brief Summary: This was an open label first in human Phase I/II multicentre study of GT005 in subjects with Macular Atrophy due to Age-related macular degeneration (AMD).

Detailed Description: This was an open label first-in-human Phase I/II multicenter study to evaluate the safety, dose response and efficacy of GT005 in participants with Geographic atrophy (GA) due to Age-related macular degeneration (AMD).

The study treatment GT005 consists of an Adeno-associated virus serotype 2 (AAV2) expressing human complement factor I (hCFI). The treatment was administered as a single subretinal administration in one eye - the "study eye". Both eyes were assessed at the screening visit. If both eyes meet the eligibility criteria, the study eye will be the worse seeing eye, or the eye with the largest geographic atrophy (GA) lesion area for eyes with equivalent visual acuity, unless the participant (in consultation with the surgeon) expresses an alternative preference.

The study was conducted in 4 parts: in Part 1 and Part 2 GT005 was administered subretinally via transvitreal procedure; in Part 3 and 4 GT005 was delivered subretinally via a suprachoroidal cannulation with the Orbit Subretinal delivery system (SDS). The Orbit SDS is a 510(k) cleared device in the US, whereby Parts 3 and 4 were only conducted at US sites. The treatment consisted in 3 dose levels: low dose, 2E10 vector genomes (vg); medium dose, 5E10 vg; and high dose, 2E11 vg.

The study consisted of up to 13 visits over a 5-year period. All participants were assessed for the occurrence of treatment emergent adverse events (AE)s at each visit and underwent visual function and retinal imaging assessments 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, nternational Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and the Food and Drug Administration (FDA) guidance.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 56

Inclusion Criteria

Able and willing to give consent to study participation
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)
Cohorts 1 to 6: GA lesion(s) total size in the study eye must be ≥1.25mm2 and ≤17.5mm2.

Cohort 7: GA lesion(s) total size in the study eye must be ≥1.25mm2
GA lesion(s) in the study eye must reside completely within the FAF fundus image
Cohorts 1 to 3: BCVA of ≤50 letters (6/36 Snellen acuity equivalent or worse) using ETDRS charts in the study eye Cohorts 4 to 7: BCVA of ≥24 letters (6/95 and 20/320 Snellen acuity equivalent or better) using ETDRS charts in the study eye
Aged ≥55 years
Able to attend all study visits and complete the study procedures
Women of child-bearing potential need to have a negative urine pregnancy test within two weeks prior to receiving the drug. 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

Have evidence or history of Choroidal Neovascularisation (CNV) in the study eye. Subjects 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
Presence of moderate/severe non-proliferative diabetic retinopathy or worse 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 aluminum 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 more than two topical agents; a history of glaucoma-filtering or valve surgery is also excluded
Axial myopia of greater than -8 diopters in the study eye
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
Have received a gene or cell therapy at any time
Have a contraindication to the specified protocol corticosteroid regimen
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
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
Cohorts 5 to 7 only: presence of metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, and other implanted electrodes or stimulators

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
GT005 2E10 vg via Transvitreal Procedure	GT005	GT005 2E10 vg via Transvitreal Procedure
GT005 5E10 vg via Transvitreal Procedure	GT005	GT005 5E10 vg via Transvitreal Procedure
GT005 2E11 vg via Transvitreal Procedure	GT005	GT005 2E11 vg via Transvitreal Procedure

Primary Outcome Measures

Name	Time	Method
Ocular Treatment Emergent Adverse Events by Primary System Organ Class and Preferred Term for the Study Eye	Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 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.
Summary of Non-Ocular Treatment Emergent Adverse Events	Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 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.
Summary of Ocular Serious Treatment-Emergent Adverse Events in the Study Eye by System Organ Class and Preferred	Adverse events are reported from the single dose of study medication administration until end of study treatment plus 240 weeks post treatment, up to a maximum timeframe of approximately 240 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.

Secondary Outcome Measures

Name	Time	Method
Best Corrected Visual Acuity (BCVA) (in Early Treatment Diabetic Retinopathy Study (ETDRS) Letters) in the Study Eye	Up to Week 240	Best corrected visual acuity (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.
Low-Luminance Deficit Best Corrected Visual Acuity (BCVA-LLVA) (in Early Treatment Diabetic Retinopathy Study (ETDRS) Letters) in the Study Eye	Up to Week 240	Low-Luminance Deficit best corrected visual acuity (BCVA-LLVA) 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.
Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Bivariate Contour Ellipse Area (BCEA) 63 Area (deg2)	Up to Week 240	Macular sensitivity as assessed by mesopic Microperimetry. Mesopic Microperimetry (MP) Bivariate contour ellipse area (BCEA) 63 Area.
Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Bivariate Contour Ellipse Area (BCEA) 95 Area (deg2)	Up to Week 240	Macular sensitivity as assessed by mesopic Microperimetry. Mesopic Microperimetry (MP) Bivariate contour ellipse area (BCEA) 95 Area.
Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Mean Sensitivity Decibel (dB)	Up to Week 240	Macular sensitivity as assessed by mesopic Microperimetry
Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Number of Scotomatous Points	Up to Week 240	Macular sensitivity as assessed by mesopic Microperimetry
Macular Sensitivity Parameters by Mesopic Microperimetry (MP) Over Time in the Study Eye - MP Percent Fixation Loss (%)	Up to Week 240	Macular sensitivity as assessed by mesopic Microperimetry
Change From Baseline Over Time in Square Root of Geographic Atrophy Area Size (mm) Via FAF in the Study Eye	Up to Week 240	Change from baseline in GA size as assessed by fundus autofluorescence
Delivery of GT005 to the Subretinal Space - Rate of Successful Delivery, % (US Only) Via the Orbit Subretinal Delivery System (SDS) Device	Day 1	The rate of successful delivery is an evaluation limited to the administration performed using the Orbit Subretinal Delivery System (SDS) device, which is a 510(k) cleared device in the US. The rate of successful delivery of GT005 is the number of full doses delivered divided by number of Orbit devices used. This endpoint evaluates the surgical procedure with the Orbit device, and it is independent of the dose administered, as the volume of GT005 administered was consistent across all arms and cohorts. The delivery was attempted in 28 pts but was only successful in 25 pts. Of 3 pts where the GT005 delivery via Orbit SDS arms was not successful, 2 were treated via the transvitreal procedure, and 1 was disc. from treatment. (For 1 of the 3 pts, BSS delivery was successful, but not GT005 delivery.) In all other efficacy tables, these 2 pts who were treated via the transvitreal procedure are included in the 1 of the 3 Transvitreal Procedure arms and not 1 of the 2 Orbit SDS arms.
Delivery of Balanced Salt Solution (BSS) or BSS PLUS (BSS+) to the Subretinal Space - Rate of Successful Delivery, % (US Only) Via the Orbit Subretinal Delivery System (SDS) Device	Day 1	The rate of successful delivery is an evaluation limited to the administration performed using the Orbit Subretinal Delivery System (SDS) device, which is a 510(k) cleared device in the US. The rate of successful delivery of BSS was the number of full doses delivered divided by number of Orbit devices used. This endpoint evaluates the surgical procedure with the Orbit device, and it is independent of the dose administered, as the volume of BSS administered was consistent across all arms and cohorts. The delivery was attempted in 28 pts but was only successful in 25 pts. Of 3 pts where the GT005 delivery via Orbit SDS arms was not successful, 2 were treated via the transvitreal procedure, and 1 was disc. from treatment. (For 1 of the 3 pts, BSS delivery was successful, but not GT005 delivery.) In all other efficacy tables, these 2 pts who were treated via the transvitreal procedure are included in the 1 of the 3 Transvitreal Procedure arms and not 1 of the 2 Orbit SDS arms.
Summary of Ocular Treatment-Emergent Adverse Events Related to Surgical Procedure in the Study Eye	Day 1	Subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS. 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.
Summary of Non-Ocular Treatment-Emergent Adverse Events Related to Surgical Procedure	Day 1	Subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS. 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.
Summary of Ocular Serious Treatment-Emergent Adverse Events Related to Surgical Procedure in the Study Eye	Day 1	Subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS. 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.
Summary of Non-Ocular Serious Treatment-Emergent Adverse Events Related to Surgical Procedure	Day 1	Subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS. 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.

Trial Locations

Locations (13): Midwest Eye Institute
🇺🇸
Indianapolis, Indiana, United States
Wolfe Eye Clinic
🇺🇸
West Des Moines, Iowa, United States
Ophthalamic Consultants of Boston (OCB)
🇺🇸
Boston, Massachusetts, United States
Pepose Vision Institute
🇺🇸
Chesterfield, Missouri, United States
Sierra Eye Associates
🇺🇸
Reno, Nevada, United States
Cincinnati Eye Institute
🇺🇸
Cincinnati, Ohio, United States
Mid-Atlantic Retina
🇺🇸
Philadelphia, Pennsylvania, United States
Bristol Eye Hospital
🇬🇧
Bristol, United Kingdom
Retina Clinic London
🇬🇧
London, United Kingdom
Moorfields Eye Hospital
🇬🇧
London, United Kingdom
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Midwest Eye Institute
🇺🇸Indianapolis, Indiana, United States