Efficacy and Safety Study of Ixoberogene Soroparvovec (Ixo-vec) in Participants With Neovascular Age-Related Macular Degeneration

Phase 3

Recruiting

• Conditions: Neovascular Age-Related Macular Degeneration (nAMD); Wet AMD
• Interventions: Genetic: Ixo-vec; Drug: Aflibercept

• Registration Number: NCT06856577
• Lead Sponsor: Adverum Biotechnologies, Inc.

Brief Summary

This is a multi-center, randomized, double-masked, active-comparator-controlled, Phase 3 study in a broad participant population (treatment-naïve and treatment-experienced) with neovascular (wet) age-related macular degeneration (nAMD). The study will evaluate a single intravitreal (IVT) injection of Ixo-vec compared to an active comparator. The primary endpoint of this study is the mean change in best corrected visual acuity (BCVA) of Ixo-vec compared to an active comparator measured at an average of Weeks 52 and 56.

Safety, tolerability, and efficacy will be evaluated throughout the study.

Detailed Description

The primary objective of this study is to evaluate the non-inferiority in efficacy of a single intravitreal (IVT) injection of Ixo-vec 6 x 10\^10 vector genome (vg)/eye compared to an active comparator.

Neovascular or wet age-related macular degeneration (nAMD) is a degenerative ocular disease associated with the infiltration of abnormal blood vessels in the retina from the underlying choroid layer and is a leading cause of blindness in patients over 65 years of age. The abnormal angiogenic process in nAMD is stimulated and modulated by vascular endothelial growth factor (VEGF). Treatment of nAMD requires frequent intravitreal (IVT) injections of VEGF inhibitors (anti-VEGF) administered every 4-16 weeks. Ixo-vec (also known as ADVM-022 or AAV.7m8-aflibercept) is a gene therapy product being developed for the treatment of nAMD. Ixo-vec is designed to reduce the current treatment burden which often results in undertreatment and vision loss in patients with nAMD receiving anti-VEGF therapy in clinical practice.

Safety, tolerability, and efficacy will be evaluated throughout this study. The primary endpoint of this study is the mean change in best corrected visual acuity (BCVA) of Ixo-vec compared to an active comparator measured at an average of Weeks 52 and 56 post-treatment.

Study Timeline

• Study First Submitted: 2025-02-26
• Study First Submitted QC: 2025-02-26
• Study Start: 2025-02-28
• Study First Posted: 2025-03-04
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-16
• Last Update Posted: 2025-05-18
• Primary Completion: 2030-03-25
• Study Completion: 2030-03-25

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 284

Inclusion Criteria

1. Able and willing to provide informed consent (or have a legally authorized representative who is able and willing to provide informed consent) prior to any study assessments and procedures and comply with the study requirements and visits.
2. Male or female with a diagnosis of CNV secondary to nAMD in the study eye, with nAMD disease activity at Screening Visit 1.
3. At least 50 years old at Screening Visit 1.
4. An Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA letter score of 35 - 78 (approximate Snellen equivalent of 20/200 to 20/32) in the study eye at Screening Visit 1.
5. Demonstrated a meaningful anatomic response to anti-VEGF therapy during screening
6. Able to reliably use eye drops per protocol

Exclusion Criteria

General Exclusion Criteria

1. History of a medical condition giving reasonable suspicion of a condition that contraindicates the use of Ixo-vec, compromises the participant's ability to comply with the planned study activities, or that might affect the interpretation of the results of the study or render the participant at high risk for treatment complications in the opinion of the Investigator. History of severe coronavirus disease (COVID-19) infection may meet this exclusion criteria if, in the opinion of the Investigator, it is likely to lead to any important complications.

2. Received any prior gene therapy.

3. Prior treatment with any non-gene therapy investigational medicinal product (IMP) or medical device in the study eye within 3 months of Screening Visit 1 or 5 half-lives of the IMP prior to dosing with Ixo-vec, whichever is longer.

4. Female participants who are pregnant or breastfeeding or who intend to become pregnant or breastfeed in the future.

5. History or evidence of any of the following cardiovascular diseases:

   1. Myocardial infarction in the 6-month period prior to Day 1.
   2. Uncontrolled hypertension defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
   3. Stroke in the 6-month period prior to Day 1.

6. History of ongoing bleeding disorders

7. Use of systemic immunosuppressive drugs within 90 days prior to Screening Visit 1.

8. Evidence of poorly controlled diabetes or glycated hemoglobin (HbA1c) ≥ 8.0% during screening

Ocular Exclusion Criteria

1. Any active ocular or periocular infection in the study eye from Screening Visit 1.

2. History or evidence of the following in the study eye:

   1. Intraocular or refractive surgery within 90 days prior to Screening Visit 1 (Day -56 to Day -49).
   2. Any previous penetrating keratoplasty or vitrectomy.
   3. Any previous panretinal photocoagulation.
   4. Any previous submacular surgery, other surgical intervention (including port delivery system) or laser treatment for age related macular degeneration.

3. Any history or evidence of retinal detachment (with or without repair) or retinal pigment epithelium rip/tear in the study eye, as determined by the Investigator during screening or at Day 1.

4. Uncontrolled ocular hypertension or glaucoma in the study eye from Screening Visit 1 to Week 1.

5. Any history of intraocular pressure (IOP) elevation related to topical steroid administration in either eye.

6. Any history of uveitis or inflammation (grade trace or above) except mild anticipated post operative inflammation that resolved in either eye.

7. Any history of treatment with complement inhibitors for geographic atrophy in the study eye.

8. Known history of ocular herpes simplex virus, varicella-zoster virus, or cytomegalovirus, including viral uveitis, retinitis, or keratitis in either eye.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ixo-vec	Ixo-vec	Participants will receive 3 monthly loading doses of aflibercept 2 mg IVT, a single IVT injection of Ixo-vec 6 x 10\^10 vg/eye at Week 1, and sham injections every 8 weeks
Ixo-vec	Aflibercept	Participants will receive 3 monthly loading doses of aflibercept 2 mg IVT, a single IVT injection of Ixo-vec 6 x 10\^10 vg/eye at Week 1, and sham injections every 8 weeks
Aflibercept	Aflibercept	Participants will receive 3 monthly loading doses of aflibercept 2 mg IVT, a sham injection at Week 1, and aflibercept 2 mg IVT every 8 weeks.

Primary Outcome Measures

Name	Time	Method
Mean Change from Baseline in Best-corrected Visual Acuity (BCVA) Post Study Drug Administration Based on an Average at Weeks 52 and 56	Baseline, Week 52 and Week 56	BCVA will be measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart.

Secondary Outcome Measures

Name	Time	Method
Mean Number of Aflibercept IVT Injections Received	Through Week 56
Percentage of Participants with worsened BCVA	Through Week 56	BCVA measured by ETDRS
Percentage of Participants with improved BCVA	Through Week 56	BCVA measured by ETDRS
Mean Change in BCVA from Baseline to Week 56	Through Week 56	BCVA measured by ETDRS
Percentage of Participants with BCVA of 73 Letters or More at Each Visit Starting at Week 4	Week 4 through Week 56
Mean Change in Central Subfield Thickness (CST) from Baseline to Week 56	Through Week 56	CST as measured by spectral domain optical coherence tomography (SD-OCT)
Mean Change in CST from Baseline to Each Post-baseline Visit	Through Week 56	CST as measured by SD-OCT
Percentage of Participants with CST ≤ 300 μm from Baseline to Each Post-baseline Visit Through Week 56	Through Week 56	CST will be assessed by a CRC using SD-OCT
Mean Number of CST Fluctuations > 50 μm from Baseline Over Time Through Week 56	Baseline to Week 56	CST will be assessed by a CRC using SD-OCT images and the mean number of fluctuations with thickness of more than 50 μm will be summarized
Percentage of Participants with CST Fluctuations > 50 μm from Baseline Over Time Through Week 56	Through Week 56	CST will be assessed using SD-OCT
Percent Reduction in Annualized Anti-Vascular Endothelial Growth Factor (VEGF) Injections	Through Week 56
Percentage of Participants who were Supplemental Aflibercept Injection-free	Through Week 56
Percentage of Participants who Received 0 or 1 Supplemental Aflibercept Injection	Through Week 56
Mean Change in Area of Choroidal Neovascularization (CNV) Lesion from Baseline to Week 56	Baseline to Week 56	CNV is the infiltration of abnormal blood vessels in the retina from the underlying choroid layer. It will be assessed by a CRC using SD-OCT.
Mean Change in Macular Volume from Baseline to Week 56	Baseline to Week 56	Macular volume will be measured as part of the full ophthalmic examination.
Percentage of Participants without Intraretinal Fluid (IRF)	Through Week 56	IRF will be assessed using SD-OCT
Percentage of Participants without Subretinal Fluid (SRF)	Through Week 56	SRF will be assessed using SD-OCT
Percentage of Participants Without IRF and/or SRF	Through Week 56	IRF and SRF will be assessed using SD-OCT
Time to No IRF and SRF	Through Week 56	IRF and SRF will be assessed using SD-OCT
Time to Sustain Dry Retina	Through Week 56	Dry retina is defined as no IRF and SRF (i.e. absence of both) maintained for 2 consecutive visits.
Number of Participants who Experienced Ocular Adverse Events	Through Week 56	The number of participants who experience an ocular adverse event will be summarized.
Number of Participants who Experienced Mild, Moderate or Severe Ocular Adverse Events	Through Week 56	The number of participants who experience a mild, moderate or severe ocular adverse event will be summarized.
Number of Participants who Experienced Non-ocular Adverse Events	Through Week 56	The number of participants who experience a non-ocular adverse event will be summarized.
Number of Participants who Experienced Mild, Moderate or Severe Non-ocular Adverse Events	Through Week 56	The number of participants who experience a mild, moderate or severe non-ocular adverse event will be summarized.
Mean Change in 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) Total and Subscale Scores	Baseline, Week 28 and Week 56	The NEI VFQ-25 measures vision-targeted patient-reported outcomes of individuals with chronic eye diseases. It comprises 25 questions. The assessment generates an overall composite score and includes the following subscales: global vision rating, difficulty with near vision activities, difficulty with distance vision activities, limitations in social functioning due to vision, role limitations due to vision, dependency on others due to vision, mental health symptoms due to vision, driving difficulties, limitations with peripheral and color vision, and ocular pain. A decrease in the NEI VFQ-25 score represents an improvement in disease severity.

Trial Locations

Locations (32)

Adverum Clinical Site 175; 🇺🇸 Santa Barbara, California, United States

Adverum Clinical Site 178; 🇺🇸 Phoenix, Arizona, United States

Adverum Clinical Site 159; 🇺🇸 Tucson, Arizona, United States

Adverum Clinical Site 198; 🇺🇸 Springdale, Arkansas, United States

Adverum Clinical Site 126; 🇺🇸 Phoenix, Arizona, United States

Adverum Clinical Site 100; 🇺🇸 Beverly Hills, California, United States

Adverum Clinical Site 109; 🇺🇸 Bakersfield, California, United States

Adverum Clinical Site 116; 🇺🇸 Lakewood, Colorado, United States

Adverum Clinical Site 165; 🇺🇸 Waterford, Connecticut, United States

Adverum Clinical Site 176; 🇺🇸 Fort Lauderdale, Florida, United States

Adverum Clinical Site 169; 🇺🇸 Fullerton, California, United States

Adverum Clinical Site 221; 🇺🇸 Fort Myers, Florida, United States

Adverum Clinical Site 213; 🇺🇸 Orlando, Florida, United States

Adverum Clinical Site 168; 🇺🇸 Jacksonville, Florida, United States

Adverum Clinical Site 124; 🇺🇸 Pompano Beach, Florida, United States

Adverum Clinical Site 183; 🇺🇸 South Miami, Florida, United States

Adverum Clinical Site 179; 🇺🇸 Oak Forest, Illinois, United States

Adverum Clinical Site 204; 🇺🇸 Hagerstown, Maryland, United States

Adverum Clinical Site 216; 🇺🇸 Madison, Mississippi, United States

Adverum Clinical Site 209; 🇺🇸 Wake Forest, North Carolina, United States

Adverum Clinical Site 207; 🇺🇸 Oak Park, Illinois, United States

Adverum Clinical Site 197; 🇺🇸 Hagerstown, Maryland, United States

Adverum Clinical Site 181; 🇺🇸 Erie, Pennsylvania, United States

Adverum Clinical Site 122; 🇺🇸 West Columbia, South Carolina, United States

Adverum Clinical Site 123; 🇺🇸 Abilene, Texas, United States

Adverum Clinical Site 127; 🇺🇸 Austin, Texas, United States

Adverum Clinical Site 194; 🇺🇸 Dallas, Texas, United States

Adverum Clinical Site 162; 🇺🇸 McAllen, Texas, United States

Adverum Clinical Site 185; 🇺🇸 San Antonio, Texas, United States

Adverum Clinical Site 107; 🇺🇸 The Woodlands, Texas, United States

Adverum Clinical Site 199; 🇺🇸 Lynchburg, Virginia, United States

Adverum Clinical Site 187; 🇺🇸 Wausau, Wisconsin, United States