FOCUS: First in Human Study to Evaluate the Safety and Efficacy of GT005 Administered in Subjects With Dry AMD

• ClinicalTrials.gov Identifier: NCT03846193
• Recruitment Status: Active, not recruiting
• First Posted: February 19, 2019
• Last Update Posted: December 1, 2022
• Sponsor: Gyroscope Therapeutics Limited
• Collaborator: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Gyroscope Therapeutics Limited

Tracking Information

• First Submitted Date: February 13, 2019
• First Posted Date: February 19, 2019
• Last Update Posted Date: December 1, 2022
• Actual Study Start Date: December 17, 2018
• Estimated Primary Completion Date: May 23, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 10, 2022)

Incidence of ocular and non-ocular Treatment Emergent AEs (TEAEs) and Treatment-Emergent Serious AEs (TESAEs) Severe Adverse Events (TEAE/TESAE) [ Time Frame: 48 weeks ]

Proportion of patients with TEAEs/TESAEs after subretinal injection of GT005

Original Primary Outcome Measures (submitted: February 15, 2019)

Incidence and severity of Treatment Emergent Adverse Events /Treatment Emergent Severe Adverse Events (TEAE/TESAE) [ Time Frame: 48 weeks ]

Proportion of patients with TEAEs/TESAEs after subretinal injection of GT005

Current Secondary Outcome Measures (submitted: October 10, 2022)

• Visual Acuity [ Time Frame: 48 weeks ]
  Change from baseline in BCVA (Best Corrected Visual Acuity) and LLVA (Low Luminance Visual Acuity) score via ETDRS (Early Treatment Diabetic Retinopathy Study) chart
• Macular Sensitivity [ Time Frame: 48 weeks ]
  Change from baseline in macular sensitivity as assessed by mesopic Microperimetry
• Geographic Atrophy [ Time Frame: 48 weeks ]
  Change from baseline in GA size as assessed by fundus autofluorescence
• Rate of successful delivery of Balanced Salt Solution (BSS) or BSS PLUS to the subretinal space (US only) [ Time Frame: Day 1 ]
  Proportion of subjects with successful delivery of BSS or BSS PLUS to subretinal space
• Rate of successful delivery of GT005 to the subretinal space (US only) [ Time Frame: Day 1 ]
  Proportion of subjects with successful delivery of GT005 to subretinal space
• Incidence of device-related AEs and SAEs (US only) [ Time Frame: Day 1 ]
  Proportion of subjects with device related AEs and SAEs after subretinal delivery with Orbit SDS

Original Secondary Outcome Measures (submitted: February 15, 2019)

• Geographical Atrophy (GA) Size [ Time Frame: 48 weeks ]
  Change from baseline in GA size measured in mm2
• Retinal Drusen Volume [ Time Frame: 48 weeks ]
  Change from baseline in retinal drusen volume measured in mm3
• Macular Sensitivity [ Time Frame: 48 weeks ]
  Change from baseline in macular sensitivity measured in decibels (DB)
• Monocular Reading Speed [ Time Frame: 48 weeks ]
  Change from baseline in monocular reading speed measured in words/min
• Vector Shedding [ Time Frame: 48 weeks ]
  Change from baseline in vector titres measured in vector genome/ml
• Complement factors [ Time Frame: 48 weeks ]
  Change from baseline in levels of complement factors, measured in nanograms/ml

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: FOCUS: First in Human Study to Evaluate the Safety and Efficacy of GT005 Administered in Subjects With Dry AMD
• Official Title: FOCUS: An Open Label First in Human Phase I/II Multicentre Study to Evaluate the Safety, Dose Response and Efficacy of GT005 Administered as a Single Subretinal Injection in Subjects With Macular Atrophy Due to AMD
• Brief Summary: This is an open label first in human Phase I/II multicentre study of GT005 in subjects with Macular Atrophy due to AMD
• Detailed Description: This study will evaluate the safety, the dose response and efficacy (anatomical and functional visual outcomes) of three doses of GT005 administered as a single subretinal injection in genetically defined subjects with Macular Atrophy due to Age-related Macular Degeneration (AMD). Following consent, subjects will undergo a number of ophthalmic and clinical assessments to determine eligibility for inclusion in the study. Once eligibility is confirmed, subjects will be enrolled, receive treatment, and will be followed for 48 weeks, with the option to be followed for a further 4 years in long-term follow up after completing week 48.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

A dose escalation study of the safety and efficacy of a single subretinal injection of GT005 in subjects with Macular Atrophy due to AMD

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

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

Intervention

• Biological: GT005
  A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor
• Device: GT005/ Device: Orbit™ Subretinal Delivery System

  A recombinant non-replicating Adeno-Associated Viral (AAV) vector encoding a human complement factor

  Device: Orbit™ Subretinal Delivery System

Study Arms

• Experimental: GT005 Dose 1
  A single dose of GT005 will be administered via subretinal injection
  Intervention: Biological: GT005
• Experimental: GT005 Dose 2
  A single dose of GT005 will be administered via subretinal injection
  Intervention: Biological: GT005
• Experimental: GT005 Dose 3
  A single dose of GT005 will be administered via subretinal injection
  Intervention: Biological: GT005
• Experimental: GT005 Dose 1, 2 or 3
  A single dose of GT005 will be administered via subretinal injection. This dose will be determined by dose levels determined to be tolerable in Arms 1,2 and 3
  Intervention: Biological: GT005
• Experimental: GT005 Dose 2 with Orbit Subretinal Delivery System
  A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach
  Intervention: Device: GT005/ Device: Orbit™ Subretinal Delivery System
• Experimental: GT005 Dose 3 with Orbit Subretinal Delivery System
  A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach
  Intervention: Device: GT005/ Device: Orbit™ Subretinal Delivery System
• Experimental: GT005 Dose 1, 2 or 3 with Orbit Subretinal Delivery Sysem
  A single dose of GT005 will be administered with subretinal injection via suprachoroidal cannulation approach
  Intervention: Device: GT005/ Device: Orbit™ Subretinal Delivery System

• Publications *: Dreismann AK, McClements ME, Barnard AR, Orhan E, Hughes JP, Lachmann PJ, MacLaren RE. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021 May;28(5):265-276. doi: 10.1038/s41434-021-00239-9. Epub 2021 Mar 10.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 10, 2022): 56
• Original Estimated Enrollment (submitted: February 15, 2019): 10
• Estimated Study Completion Date: January 19, 2027
• Estimated Primary Completion Date: May 23, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Able and willing to give consent to study participation
2. 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)

3. 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

4. GA lesion(s) in the study eye must reside completely within the FAF fundus image
5. 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
6. Aged ≥55 years
7. Able to attend all study visits and complete the study procedures
8. 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:

1. 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
2. Presence of moderate/severe non-proliferative diabetic retinopathy or worse in the study eye
3. Have history of vitrectomy, sub-macular surgery, or macular photocoagulation in the study eye
4. 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
5. Have clinically significant cataract that may require surgery during the study period in the study eye
6. 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
7. Axial myopia of greater than -8 diopters in the study eye
8. 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
9. Have received a gene or cell therapy at any time
10. Have a contraindication to the specified protocol corticosteroid regimen
11. Are unwilling to use two forms of contraception (one of which being a barrier method) for 90 days post-dosing, if relevant
12. 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
13. 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
14. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT03846193
• Other Study ID Numbers: GT005-01
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Gyroscope Therapeutics Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Gyroscope Therapeutics Limited
• Original Study Sponsor: Same as current
• Collaborators: Novartis Pharmaceuticals

Investigators

• Study Director: Chief Medical Officer; Novartis Pharmaceuticals

• PRS Account: Gyroscope Therapeutics Limited
• Verification Date: November 2022