ADVM-022 Intravitreal Gene Therapy for DME

Phase 2

Completed

Conditions: Diabetic Macular Edema
Diabetic Retinopathy

Interventions: Biological: 6E11 vg/eye of ADVM-022
Biological: 2E11 vg/eye of ADVM-022
Biological: Aflibercept

Registration Number: NCT04418427

Lead Sponsor: Adverum Biotechnologies, Inc.

Brief Summary: A Phase 2, Multi-Center, Randomized, Double-Masked\*, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects with Diabetic Macular Edema \[INFINITY\]

Detailed Description: ADVM-022 (also known as Ixo-vec and AAV.7m8-aflibercept) is an investigational gene therapy product developed for the treatment of serious retinal vascular diseases including Diabetic Macular Edema (DME), a vision-threatening complication of diabetic retinopathy. DME can affect up to 10% of individuals with both type 1 and type 2 diabetes mellitus. Current therapies for treating DME include anti-vascular endothelial growth factor (anti-VEGF) agents that require frequent and long-term intravitreal (IVT) injections to achieve and maintain efficacy. ADVM-022 is intended provide sustained intraocular expression of aflibercept from a single IVT injection to potentially reduce the current treatment burden and prevent disease progression and vision loss due to undertreatment.

This Phase 2, randomized, controlled study (INFINITY) enrolled 36 eligible participants with DME. The participants were randomized to receive one of the two dose levels of ADVM-022 or assigned to the control arm to receive a sham ocular injection with a preceding aflibercept injection. Participants randomized to the ADVM-022 arms were assigned to receive a preceding aflibercept or sham ocular injection. All participants were monitored regularly for disease activity and may have received supplemental aflibercept based on predefined retreatment criteria. All participants were to be followed over a 96- week follow-up period.

To enhance safety monitoring for participants in this study, the sponsor unmasked treatment assignment (in April 2021) due to the occurrence of a suspected unexpected serious adverse reaction (SUSAR) which occurred early in the study in the high dose (ADVM-022 6E11 vg/eye) arm. Interpretation of the results of this study should consider the potential confounding nature of this unmasking in the context of the observed dose-limiting events and the associated additional use of topical/intravitreal/systemic steroids, particularly in the high dose ADVM-022 arm.

In this study ADVM-022 (Ixo-vec) demonstrated improved efficacy across endpoints, reducing the need for supplemental aflibercept in DME management and demonstrating a clinically meaningful delay in DME worsening and improved outcomes across multiple endpoints compared to the control arm (sham + Aflibercept). However, the benefit of the ADVM-022 6E11 vg/eye dose was affected by dose-limiting toxicities in some participants. In terms of safety outcomes, the most common ADVM-022-related adverse events were mild-to-moderate intraocular inflammation, a known and expected side effect of ocular gene therapy, which was generally responsive to corticosteroid eye drops. No Ixo-vec-related events were reported in the fellow eye or systemically, indicating no off-target effects.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

Inclusion Criteria

Age ≥ 18
Type 1 or Type 2 diabetes mellitus
Willing and able to provide informed consent
Vision impairment due to center involving diabetic macular edema

Exclusion Criteria

Uncontrolled diabetes defined as HbA1C >10%, or history of diabetic ketoacidosis within 3 months prior to randomization; or subjects who, within the last 3 months, initiated intensive insulin treatment (a pump or multiple daily injection) or plan to do so in the next 3 months.
Acute coronary syndrome, myocardial infarction or coronary artery revascularization, CVA, TIA in the last 6 months
Uncontrolled hypertension defined as average SBP ≥160 mmHg or an average DBP ≥100 mmHg
Known severe renal impairment
High risk Proliferative Diabetic Retinopathy
History of retinal disease in the study eye other than diabetic retinopathy
History of retinal detachment (with or without repair) in the study eye
History of vitrectomy, trabeculectomy, or other filtration surgery in the study eye
Any prior focal or grid laser photocoagulation or any prior PRP in the study eye
Current or planned pregnancy or breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	6E11 vg/eye of ADVM-022	6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
2	Aflibercept	2E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
1	Aflibercept	6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
2	2E11 vg/eye of ADVM-022	2E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
3	Aflibercept	Aflibercept 2mg IVT

Primary Outcome Measures

Name	Time	Method
Time to Worsening of DME Disease Activity in the Study Eye.	Day 1 through 96 weeks	Time to worsening of DME disease activity in the study eye through 96 weeks. Time to worsening of DME disease activity defined by either: An increase in CST \> 50 µm as assessed by SD-OCT compared to the lower of the two CST measurements recorded at Day 1 or Week 4; A loss of \> 5 letters in BCVA due to worsening DME disease activity compared to the higher of the two BCVA measurements recorded at Day 1 or Week 4. Number of weeks was relative to Day 1.

Secondary Outcome Measures

Name	Time	Method
Incidence of 2-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time	From Day 1 through 96 weeks	Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step worsening indicates a worsening across 2 steps of the 13-step scale. Note: 2-step worsening in DRSS was observed in 2 participants in both the control arm and the ADVM-022 6E11 vg/eye arm. These participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation).
Incidence of 3-step Worsening in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time	From Day 1 through 96 weeks	Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 with higher scored indicating more advanced stages of Diabetic Retinopathy. The incidence of 3-step worsening in DRSS score over time at Week 96 is presented. Visits with a 3-step or greater worsening in DRSS were considered separate events. Note: 3-step worsening in DRSS was observed in one participant each in the control arm and the ADVM-022 6E11 vg/eye arm. Both participants experienced ocular adverse events which may have contributed, at least in part, to the worsening in DRSS. This included one participant in the ADVM-022 6E11 vg/eye arm who had a SUSAR of Hypotony of eye (secondary to intraocular inflammation).
Occurrence of Any Vision Threatening Complications in the Study Eye (Anterior Segment Neovascularization, Vitreous Hemorrhage, or Any Other High-risk Proliferative DR, or Tractional Retinal Detachment) Over Time Through Week 96	From Day 1 through 96 weeks	Occurrence of any vision threatening complication over time though 96 weeks. Results present the incidence of participants who experienced "Any Vision Threatening Complications" (defined as any Vitreous Haemorrhage adverse event (AE), Anterior Segment Neovascularization AE, High-risk proliferative DR (defined as DSSR \>= 71), or Tractional Retinal Detachment AE) in the study eye from Day 1 through 96 weeks. Note: AEs of Vitreous Haemorrhage and High-risk proliferative DR were reported in 1 participant in the control arm and in 2 separate participants in the 6E11 vg/eye arm. No AE of Tractional Retinal Detachment or Anterior Segment Neovascularization occurred.
Incidence of CST <300 μm Over Time Through Week 96 in the Study Eye	Day 1 through 96 weeks	Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Incidence of participants with Central subfield thickness of less than 300 μm over time in the study eye through Week 96 is presented.
Incidence of Ocular Adverse Events (AEs)	96 weeks	Incidence of ocular adverse events (AEs) through 96 weeks
Incidence of Non-ocular Adverse Events (AEs)	Day 1 through 96 weeks	Incidence of non-ocular adverse events (AEs) through 96 weeks.
Change From Baseline Central Subfield Thickness (CST) in Study Eye	Baseline through 96 weeks	Central subfield thickness is a measurement of the thickness of the retina in a circular area around the fovea. Least squares mean change from Baseline in central subfield thickness at Week 96 is presented for the study eye.
Change From Baseline in Best Corrected Visual Acuity (BCVA) Score Over Time in the Study Eye	96 weeks	Least squares mean change from Baseline in BCVA score over time was measured over time through week 96 in the study eye by ETDRS letters.
Frequency of Supplemental Aflibercept Injections (2 mg IVT) in the Study Eye Over Time During the Study	Day 1 through 96 weeks	Frequency of supplemental aflibercept (2 mg IVT) injections was assessed in the study eye over time during the study. Participants were analyzed according to the study treatments they actually received on Days 1 and 8. The rate of supplemental aflibercept per year = Total number of supplemental aflibercept injections / Total years at-risk (at-risk duration starting at Day 8).
Incidence of 2-step Improvement in Diabetic Retinopathy Severity Score (DRSS) in the Study Eye Over Time	From Day 1 through 96 weeks	Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 2-step improvement indicates an improvement in a participant across 2 steps of the 13-step scale.
Incidence of 3-step Improvement in DRSS (Diabetic Retinopathy Severity Score) in the Study Eye Over Time	From Day 1 through 96 weeks	Diabetic Retinopathy Severity Score was determined by the Central Reading Center using ultra-wide field color retinopathy fundus photography. The score represents a comprehensive evaluation of retinal health, including the presence of microaneurysms, hemorrhages, and other abnormalities in the retina of the study eye. The score ranges from 10 to 85 and is divided into 13-steps used to classify increasing diabetic retinopathy severity (with higher scored indicating more advanced stages of Diabetic Retinopathy). In this endpoint a 3-step improvement indicates an improvement in a participant across 3 steps of the 13-step scale.