Aflibercept Clinical Trials

What Is Aflibercept?

Aflibercept is an FDA-approved medication for diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), and other retinal conditions. It is a vascular endothelial growth factor (VEGF) inhibitor. VEGF is a protein in the body that can cause the growth of abnormal blood vessels and fluid leakage, particularly in the eye. By blocking VEGF, aflibercept helps to reduce this abnormal blood vessel growth and swelling. The medication is also being investigated for use in other eye disorders and various types of cancer.

Uses and Conditions Under Study

Aflibercept has been studied in 456 trials involving 949,127 participants since 2003. These trials investigate aflibercept for a range of conditions, primarily affecting the eye, but also for certain cancers.

• Age-Related Macular Degeneration (AMD) and Related Conditions: Aflibercept is extensively studied for forms of macular degeneration, including Neovascular Age-related Macular Degeneration (nAMD), Macular Degeneration, Wet Macular Degeneration, Age Related Macular Degeneration, Neovascular Age-Related Macular Degeneration, and Wet Age-related Macular Degeneration. These conditions are characterized by abnormal blood vessel growth in the macula, leading to vision loss. Aflibercept helps by inhibiting the VEGF protein responsible for this growth. Collectively, these conditions are being investigated in 136 trials.
• Diabetic Eye Conditions: The drug is also widely studied for complications of diabetes affecting the eye, such as Diabetic Macular Edema (DME) and Diabetic Retinopathy. DME involves swelling of the macula due to damaged blood vessels from high blood sugar, while diabetic retinopathy involves damage to blood vessels in the retina. Aflibercept aims to reduce this swelling and abnormal vessel formation. These conditions account for 96 trials.
• Other Retinal and Ocular Conditions: Aflibercept is being investigated for other eye conditions that involve fluid leakage or abnormal blood vessel growth. These include general Macular Edema (18 trials), Retinopathy of Prematurity (ROP) in preterm babies, Central Retinal Vein Occlusion (CRVO), Branch Retinal Vein Occlusion (BRVO), Polypoidal Choroidal Vasculopathy (PCV), Radiation Retinopathy, and corneal neovascularization.
• Cancer: Aflibercept, particularly its hyperosmolar form known as Zaltrap or ziv-aflibercept, is being studied in oncology. It is investigated for various cancers, including esophagogastric cancer and colon cancer, where it also targets VEGF to inhibit tumor blood vessel growth.

Dosing

Aflibercept is primarily administered as an intravitreal (IVT) injection directly into the eye for ophthalmic conditions. The most common strengths studied for eye conditions are 2 mg and 8 mg. The 2 mg dose of Eylea is approved for conditions like DME, often given as initial monthly injections followed by extended intervals, such as every 8 weeks.

A higher 8 mg dose, known as Eylea HD, has been studied to potentially prolong treatment intervals up to 16 weeks after initial loading doses. Dosing regimens often follow a "treat and extend" approach, where the interval between injections is gradually increased based on the patient's response to treatment. For example, some regimens involve three monthly loading doses, followed by injections every 4, 8, or 16 weeks.

For oncology indications, a related molecule, ziv-aflibercept (Zaltrap), is administered intravenously. Investigational doses for cancer have included various milligram per kilogram (mg/kg) amounts, such as 2 mg/kg, 4 mg/kg, or 6 mg/kg, and specific doses like 1.25 mg or 2.5 mg. Aflibercept has also been studied in pediatric populations, such as in babies with retinopathy of prematurity (ROP), though specific pediatric dosages are not detailed in the provided data.

Side Effects

In clinical trials, the most common side effect experienced by patients taking Aflibercept was diarrhea, affecting 44.0% of patients, compared to 38.6% of those on placebo. Other common side effects included:

• Stomatitis (mouth sores), which occurred in 42.9% of patients on Aflibercept versus 21.8% on placebo.
• Fatigue, reported by 40.3% of patients on Aflibercept compared to 38.0% on placebo.
• Hypertension (high blood pressure), observed in 34.4% of patients on Aflibercept versus 11.5% on placebo.
• Decreased appetite, affecting 30.5% of patients on Aflibercept compared to 24.3% on placebo.
• Weight loss, experienced by 28.8% of patients on Aflibercept versus 11.2% on placebo.
• Epistaxis (nosebleeds), occurring in 25.5% of patients on Aflibercept compared to 7.9% on placebo.
• Dysphonia (hoarseness or difficulty speaking), reported by 25.3% of patients on Aflibercept versus 4.9% on placebo.

Some side effects were less common in patients taking Aflibercept than in those on placebo, such as nausea (35.3% on Aflibercept vs 38.8% on placebo), alopecia (hair loss, 28.8% on Aflibercept vs 34.0% on placebo), vomiting (22.8% on Aflibercept vs 24.7% on placebo), and constipation (20.8% on Aflibercept vs 21.1% on placebo).

Clinical Trial Results

Non-small-cell-lung Adenocarcinoma

In a study (NCT00284141) of patients with locally advanced or metastatic platinum- and erlotinib-resistant non-small-cell-lung adenocarcinoma, treatment with Aflibercept 4.0 mg/kg was evaluated. The median overall survival was 26.9 months. Progression-free survival, assessed by an independent review committee, was a median of 11.3 weeks. Objective response, indicating tumor shrinkage, was observed in 0 participants when assessed by an independent committee, and in 2 participants when assessed by the investigator.

Wet Age-Related Macular Degeneration (AMD)

A study (NCT00320788) investigated Aflibercept injections for wet AMD. Patients receiving Aflibercept showed improvements in vision. At Week 16, the average patient gained 6.6 letters on a standard eye chart across all doses, with some doses (2.0mg every 4 weeks) showing an average gain of 10.0 letters. Central retinal/lesion thickness also decreased, with an average reduction of 160.2 µm at Week 16 across all doses. Furthermore, at Week 12, up to 25.8% of patients (on the 2.0mg every 4 weeks dose) gained at least 15 letters of vision.

Chemoresistant Advanced Ovarian Cancer

In a study (NCT00327171) of patients with chemoresistant advanced ovarian cancer, Aflibercept was administered at 2.0 mg/kg or 4.0 mg/kg. The median overall survival was 59.0 weeks for the 2.0 mg/kg dose and 49.3 weeks for the 4.0 mg/kg dose. Progression-free survival was approximately 13 weeks for both doses. The tumor marker response rate, based on the Gynecologic Cancer Intergroup (GCIG) definition, was 11.5% for the 2.0 mg/kg dose and 11.6% for the 4.0 mg/kg dose.

Recurrent Symptomatic Malignant Ascites (in Ovarian Cancer Patients)

A study (NCT00327444) in advanced ovarian cancer patients with recurrent symptomatic malignant ascites compared Aflibercept to placebo. Over 60 days, patients on Aflibercept had an average of 2.7 paracentesis procedures (fluid removal), compared to 5.1 procedures for those on placebo. The time until a repeat paracentesis was also significantly longer for patients on Aflibercept, with a mean of 55.1 days, versus 23.3 days for placebo.

Recurrent Malignant Gliomas

A trial (NCT00369590) investigated Aflibercept in patients with recurrent malignant gliomas. For patients with glioblastoma, the median overall survival was 39 weeks, and 7.7% of patients achieved progression-free survival at 6 months. For patients with anaplastic glioma, the median overall survival was 55 weeks, and 25% of patients achieved progression-free survival at 6 months.

Currently Recruiting Trials

Researchers are actively recruiting participants for a variety of clinical trials involving aflibercept, exploring its use in new ways or comparing it against other treatments for various eye conditions. These studies aim to improve patient outcomes and expand treatment options.

• A Phase 3 study, the PALLAS Trial (NCT07389980), is evaluating a personalized regimen of high-dose Aflibercept 8 mg for treatment-naive Polypoidal Choroidal Vasculopathy. This study, sponsored by Yeungnam University College of Medicine, seeks to enroll 50 participants to assess the efficacy and safety of flexible dosing intervals.
• Another Phase 3 trial (NCT07489131), sponsored by Alvotech Swiss AG, is comparing the efficacy and safety of AVT29, a proposed aflibercept HD biosimilar, against Eylea HD in participants with Diabetic Macular Edema. This randomized, double-masked study plans to enroll 256 individuals.
• EyeBiotech Ltd. is sponsoring two Phase 2/3 trials (NCT07496567 and NCT07440225) investigating a new medicine called tiespectus (MK-8748 or EYE201) for neovascular age-related macular degeneration (NVAMD). These studies compare different doses of tiespectus against aflibercept 2 mg, each targeting 960 participants.
• Adverum Biotechnologies, Inc. is conducting two Phase 3 studies (NCT07482176 and NCT06856577) to evaluate the efficacy and safety of ixoberogene soroparvovec (Ixo-vec) as a single intravitreal injection compared to aflibercept in participants with neovascular age-related macular degeneration (nAMD). Each study aims to enroll 284 participants.
• The STELLAR study (NCT07317934), a Phase 3 trial sponsored by Innostellar Biotherapeutics Co.,Ltd, is assessing the efficacy and safety of LX102 gene therapy delivered via subretinal injection in patients with nAMD, comparing it to aflibercept. This trial plans to enroll 332 participants.
• An observational study (NCT06315556) sponsored by Bayer is collecting real-world data on how aflibercept (Eylea) is used with a pediatric dosing device in 200 preterm babies with Retinopathy of Prematurity (ROP) in the United Kingdom.
• Kim's Eye Hospital is sponsoring a Phase 4 study (NCT06683950) to evaluate switching to aflibercept 8mg in 40 patients with age-related macular degeneration (ARMD) who have shown limited response to previous treatments.

Where to Participate

Clinical trials involving aflibercept are widely accessible across the United States. Research is being conducted at 444 sites in 186 cities across 41 states. Some of the cities with the highest number of recruiting sites include:

• Sacramento, California
• Austin, Texas
• Hagerstown, Maryland
• Phoenix, Arizona
• San Antonio, Texas

Eligibility for these trials is broad, welcoming participants of all genders and ages ranging from 1 to 120 years old. Healthy volunteers are generally not sought for these studies, as they focus on individuals with specific medical conditions, and children are eligible for participation in relevant trials.

Development Timeline

The journey of aflibercept in clinical research began on January 27, 2003, with its first recorded clinical trial. Since then, the drug has been the subject of an extensive research program, encompassing a total of 456 clinical trials that have collectively enrolled over 949,000 participants. The development pipeline has seen significant progression through various phases, with 103 trials reaching Phase 2, 99 in Phase 3, and 93 in Phase 4, indicating a robust and ongoing commitment to understanding its full potential.

Initially, aflibercept research explored conditions such as IBS-C and hyperphosphatemia. However, the focus quickly expanded and largely shifted to ophthalmic diseases, particularly those affecting vision. Key conditions studied include Macular Degeneration, Diabetic Retinopathy, and Neovascular Age-Related Macular Degeneration, alongside various forms of macular edema and choroidal neovascularization. The research also extended to certain types of cancer, such as Metastatic Colorectal Cancer and Metastatic Uveal Melanoma, demonstrating the drug's diverse therapeutic exploration.

Leading the development efforts have been major pharmaceutical companies, with Bayer sponsoring 56 trials and Regeneron Pharmaceuticals sponsoring 27 trials. Other significant contributors include Sanofi and the National Cancer Institute (NCI). The latest trial is projected to conclude in April 2026, highlighting the continued investigation into aflibercept's applications and efficacy.