4D-150 in Patients With Neovascular (Wet) Age-Related Macular Degeneration

Official title

A Phase 1/2 Dose-Escalation and Randomized, Controlled, Masked Expansion Trial of Intravitreal 4D-150 Gene Therapy in Adults With Neovascular (Wet) Age-Related Macular Degeneration

Overview

Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment. Substudies will evaluate the safety and tolerability of 4D-150 contralateral eye dosing and characterize vector shedding.

Detailed description

This Phase 1/2 trial is a prospective, multicenter, Phase 1/2 dose-escalation and randomized, controlled, masked expansion trial in adults with wet AMD undergoing active anti-VEGF treatment who have demonstrated a clinical response consistent with anti-VEGF activity. The trial consists of Dose Escalation, Dose Expansion, Steroid Optimization, and\[DD1.1\]\[JA1.2\] Population Extension Cohorts.

After receiving one time administration of 4D-150 by intravitreal injection (IVT), subjects will undergo assessments at monthly intervals for 24 months to assess safety and efficacy outcomes. Only subjects that received 4D-150 will then enter a long-term follow-up (LTFU) period to assess long-term safety of 4D-150 gene therapy and duration of clinical activity through year 5 (60 months).

Eligible subjects who received 4D-150 in the study eye may participate in a sub-study to evaluate one-time IVT administration of 4D-150 to the contralateral ("fellow") eye.

Additional subjects will be enrolled in a separate sub-study to characterize the vector shedding profile of one-time administration of IVT 4D-150.

In both sub-studies, subjects will undergo regular assessments to assess safety and tolerability through Week 52 and then will enter long-term follow-up for safety evaluation through year 5 (60 months).

Interventions

• Biological 4D-150 IVT
  4D-150: AAV-based gene therapy comprised of miRNA targeting VEGF-C and codon-optimized sequence encoding aflibercept
• Biological Aflibercept IVT
  Commercially available Active Comparator Other Name: Eylea

Primary outcome measures

• Incidence and severity of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), including clinically significant changes in safety parameters [Time frame: 52 weeks]

Secondary outcome measures (6)

• Time to receiving the first supplemental aflibercept injection [Time frame: 52 weeks]
• Percentage of subjects requiring supplemental aflibercept injections over 52 weeks [Time frame: 52 weeks]
• Number of supplemental aflibercept injections over 52 weeks [Time frame: 52 weeks]
• Change from baseline in BCVA over time (up to 52 weeks) as assessed using the ETDRS Visual Acuity Chart [Time frame: 52 weeks]
• Change from baseline in central subfield thickness (CST) over time (up to 52 weeks) measured by spectral domain optical coherence tomography (SD-OCT) [Time frame: 52 weeks]
• Percent Change in Annualized Mean Number of anti-VEGF IVT injections before and after the 4D-150 injection [Time frame: Before and after the 4D-150 injection (or Day 1 for the aflibercept only arm)]

Eligibility criteria

• 50 years of age

Individuals eligible to participate in the trial must meet the following inclusion criteria:

• ≥50 years of age
• Diagnosed with CNV secondary to AMD (confirmed by reading center)
• BCVA ≥34 ETDRS letters (\~20/200) in the contralateral eye, and BCVA in the study eye:
• Central subfield thickness (CST) and/or presence of subretinal or intraretinal fluid requiring continued anti-VEGF therapy in the study eye, as assessed by SD-OCT; and confirmed by a reading center):
• Study eye amenable to IVT injection
• Ability to perform tests of visual and retinal function and structure, and ability to comply with other protocol-specified procedures
• Currently receiving anti-VEGF treatment (e.g. ranibizumab, aflibercept, faricimab or bevacizumab) in the study eye AND has demonstrated a clinical response consistent with anti-VEGF activity within 12 months prior to screening:

Note: Day -7 aflibercept will be administered ≥ 4 weeks from last IVT anti-VEGF

• Subjects receiving 4D-150 agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
• Medical records available to document history of anti-VEGF therapy (dates, drugs, and dosage) for a minimum of 12 months prior to Screening
• Provide written informed consent.

Contralateral Eye Sub-study-Specific Criteria:

• Received 4D-150 in study eye-1 at least 6 months prior to Contralateral Substudy Screening Visit NOTE: Subjects who received 4D-150 in study eye-1 as part of the Shedding Substudy are also eligible to participate in the Contralateral Eye Substudy only after biological samples from all matrices were at or below the limit of quantitation for vector genomes in at least 3 consecutive measurements AND at least 6 months has passed since 4D-150 administration to study eye-1.
• Macular neovascularization (MNV) secondary to AMD in study eye-2 as assessed on historical images at any time by SD-OCT (required) and FA when available or fundus photography when available or at screening based on SD-OCT, FA and fundus photography (confirmed by the reading center)
• History of at least 1 anti-VEGF injection in study eye-2 within 6 months prior to Screening (last anti-VEGF injection must be at least 28 days prior to Screening) AND has demonstrated a clinical response consistent with anti-VEGF activity by historical OCT at any time point prior to screening with confirmed response by the reading center (Screening OCT can be confirmatory)
• BCVA between 25 and 83 ETDRS letters, inclusive (20/320 20/25 Snellen) in study eye-2
• Study eye-2 amenable to IVT injection
• BCVA ≥34 ETDRS letters (\~20/200) in the previously treated study eye-1
• Ability to comply with protocol-specified procedures and visits, in the Investigator's judgment
• Agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to study eye-2 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
• Provide written informed consent.

Shedding Substudy-specific Inclusion Criteria:

• ≥50 years of age
• Diagnosed with MNV secondary to AMD as assessed on historical images at any time by spectral domain optical coherence tomography (SD-OCT) (required) and fluorescein angiography when available or fundus photography when available or at screening based on SD-OCT, FA and fundus photography (confirmed by Reading Center)
• Best corrected visual acuity (BCVA) between 10 and 83 ETDRS letters, inclusive (\~20/640 and 20/25, respectively) in the study eye at Screening
• BCVA ≥34 ETDRS letters (\~20/200) in the contralateral eye
• Currently receiving anti-VEGF treatment (e.g. ranibizumab, aflibercept, faricimab or bevacizumab) in the study eye; minimum of 1 injection within the last 6 months (last anti-VEGF injection must be at least 28 days prior to screening) AND has demonstrated a clinical response consistent with anti-VEGF activity by historical OCT at any time prior to screening with confirmed response by the reading center (Screening OCT can be confirmatory)
• Study eye amenable to IVT injection
• Ability to perform tests of visual and retinal function and structure, and ability to comply with other protocol-specified procedures, in the Investigator's judgment
• Agree to use a barrier method (e.g. condom) during intercourse for 6 months after administration of 4D-150 to prevent fluid transmission; sexually active males should not father a child or donate sperm during this period
• Provide written informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 24 centers

• Barnet Delaney Perkins Eye Center — Phoenix
• California Retina Consultants — Oxnard
• Retinal Consultants Medical Group — Sacramento
• Colorado Retina Associates — Lakewood
• Rand Eye Institute — Deerfield Beach
• Retina Vitreous Consultants, LLP DBA Retina Group of Florida — Fort Lauderdale
• Vitreo Retinal Associates — Gainesville
• Florida Eye Associates — Melbourne
• … and 16 more centers

Puerto Rico · 1 center

• Emanuelli Research and Development Center, LLC — Arecibo

Publications

• Calton MA, Croze RH, Burns C, Beliakoff G, Vazin T, Szymanski P, Schmitt C, Klein A, Leong M, Quezada M, Holt J, Bolender G, Barglow K, Khoday D, Mason T, Delaria K, Hassanipour M, Kotterman M, Khanani AM, Schaffer D, Francis P, Kirn D. Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies. Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):1. PMID 39620832

Identifiers

NCT: NCT05197270 · 4D-150-C001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗