Eylea (Aflibercept), a VEGF Receptor Inhibitor, Receives New Indication for All Stages of Diabetic Retinopathy

2019 Payers' Guide Mid-Year Addendum - Select Drug Profiles
Lilly Ostrovsky
Medical Writer
Diabetic retinopathy is the most common cause of vision loss among patients with diabetes and the leading cause of vision impairment in adults in developed countries,1-3 affecting approximately 35.4% of people globally.2 The disease is characterized by retinal neovascularization, microaneurysms, protein exudates in the vitreous, and a steady decline in vision, all of which are driven by hyperglycemia in patients with diabetes.1,4

Diabetic retinopathy comprises 4 stages, including mild nonproliferative retinopathy; moderate nonproliferative retinopathy; severe nonproliferative retinopathy; and proliferative diabetic retinopathy.5

Mild nonproliferative retinopathy is characterized by balloonlike inflammation in the retina’s blood vessels (ie, microaneurysms), which may leak fluid into the retina. Moderate nonproliferative retinopathy occurs when vessels that feed the retina enlarge and distort. These blood vessels may lose their ability to transport blood. Severe nonproliferative retinopathy occurs when blood vessels become blocked and deprive the retina of blood, which causes these areas to secrete growth factors that signal the growth of new blood vessels.

Proliferative diabetic retinopathy, which is the most advanced stage of the disease, occurs when growth factors activate the proliferation of new blood vessels along the inside surface of the retina and into the vitreous gel, which can result in retinal detachment and lead to permanent blindness.5

The treatments for patients with diabetic retinopathy include laser photocoagulation, glucocorticoids, vitrectomy, and anti–vascular endothelial growth factor (VEGF) drugs, such as bevacizumab (Avastin; off-label use), and ranibizumab (Lucentis).1,5 The majority of patients with diabetic retinopathy require monthly injections of anti-VEGF agents for the first 6 months of treatment; injections are needed less often thereafter.5

FDA Approves Eylea for All Diabetic Retinopathy Stages

On May 13, 2019, the US Food and Drug Administration (FDA) approved aflibercept (Eylea; Regeneron) injection for the treatment of diabetic retinopathy.6,7 Aflibercept is the only VEGF inhibitor approved with 2 dosing options (every 8 weeks after 5 initial monthly injections, or every 4 weeks) for diabetic retinopathy.6

“Millions of people have been robbed of their vision due to the progression of diabetic retinopathy,” said David Brown, MD, FACS, Director of Research, Retina Consultants of Houston, and an investigator for the PANORAMA trial.6

“The prevention of worsening diabetic retinopathy with Eylea provides a compelling rationale for early treatment of patients with this disease, particularly since eyes dosed with Eylea as infrequently as every 16 weeks showed significant improvements in the pivotal PANORAMA trial,” Dr Brown added.6

Aflibercept was initially approved in 2011 for the treatment of wet age-related macular degeneration, followed by a new indication in 2012 for macular edema after central retinal vein occlusion.8,9 In 2014, aflibercept received yet another indication for the treatment of diabetic macular edema, followed by an additional approval in 2015 for diabetic retinopathy in patients with diabetic macular edema.8

Mechanism of Action

VEGF-A and placental growth factor are angiogenic factors. Binding of placental growth factor to VEGF receptor 1 can result in neovascularization and vascular permeability of endothelial cells. Aflibercept acts as a soluble decoy receptor that joins VEGF-A with placental growth factor, and thereby can stop the binding and activation of these similar VEGF receptors.7

Dosing and Administration

The recommended dose of aflibercept for patients with diabetic retinopathy is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks.7 Aflibercept may be dosed as frequently as 2 mg every 4 weeks, and some patients may need every-4-week dosing after the first 20 weeks.7

Pivotal Clinical Trial: PANORAMA

The approval of aflibercept for diabetic retinopathy was based on the randomized, multicenter, double-blind, controlled PANORAMA clinical trial involving 402 patients (mean age, 55.7 years; range, 25-85 years) with moderately severe to severe nonproliferative diabetic retinopathy without central-involved diabetic macular edema.7 All patients received 3 initial monthly 2-mg injections of aflibercept and were then randomized in a 1:1:1 ratio to receive either 1 injection after 8 weeks, followed by 1 injection every 16 weeks (cohort 2Q16); 5 monthly aflibercept 2-mg injections, followed by 1 injection every 8 weeks (cohort 2Q8); or to sham treatment.7

The primary efficacy end point was the proportion of patients who improved by ≥2 steps on the diabetic retinopathy severity scale from baseline to week 24 in the combined aflibercept groups and at week 52 in the 2Q16 and 2Q8 cohorts individually versus the sham treatment group.7 A key secondary end point was the proportion of patients who had the composite end point of proliferative diabetic retinopathy or anterior segment neovascularization through week 52 of treatment in the aflibercept cohorts versus the sham treatment group.

Overall, 65% of patients in the 2Q16 cohort and 80% of patients in the 2Q8 cohort had a ≥2-step improvement in the Early Treatment Diabetic Retinopathy Study’s Diabetic Retinopathy Severity Score from baseline (Table). Furthermore, significantly fewer patients had proliferative diabetic retinopathy in the 2Q16 cohort (4%) or 2Q8 cohort (2.4%) than in the control group (20.1%; Table).7

Table

Adverse Events

The safety of aflibercept in patients with diabetic retinopathy was assessed in the PANORAMA clinical trial in 269 patients with nonproliferative diabetic retinopathy through week 52.7 These safety data were consistent with those seen previously in the phase 3 VIVID and VISTA clinical trials in patients with diabetic macular edema.

The most common (incidence ≥5%) adverse events in patients who received aflibercept included conjunctival hemorrhage (28%), eye pain (9%), cataract (8%), vitreous floaters (6%), increased intraocular pressure (5%), corneal epithelium defect (5%), and ocular hyperemia (5%).7

Contraindications

Aflibercept is contraindicated in patients with ocular or periocular infections, in patients with active intraocular inflammation, and in those with a known hypersensitivity to aflibercept or to any of its excipients.7

Use in Specific Populations

Adequate and well-controlled studies with aflibercept have not been conducted in pregnant women. Aflibercept should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.7

There are no data regarding the presence of aflibercept in human milk, its effects on the breastfed infant, or its effects on milk production. As such, aflibercept is not recommended during breastfeeding.

Females of reproductive potential should use effective contraception before the initial dose, during treatment, and for at least 3 months after the last intravitreal injection of aflibercept.7

The safety and efficacy of aflibercept in pediatric patients have not been established.7

In clinical studies, approximately 76% of patients who received aflibercept were aged ≥65 years and approximately 46% were aged ≥75 years. No significant differences were observed in efficacy or safety with increasing age in these studies.7

Warnings and Precautions

Intravitreal injections with aflibercept have been associated with endophthalmitis and retinal detachments; therefore, proper aseptic injection technique must be used when administering aflibercept.7 Patients should be instructed to immediately report any symptoms suggestive of endophthalmitis or retinal detachment.7

Acute increases in intraocular pressure have been reported within 60 minutes of the intravitreal injection of aflibercept, as well as sustained increases in intra­ocular pressure after repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.7

Intravitreal injection with aflibercept has a potential risk for arterial thromboembolic events, including nonfatal stroke, nonfatal myocardial infarction, or vascular death.7

Conclusion

Aflibercept is the second anti-VEGF drug approved by the FDA for the treatment of patients with diabetic retinopathy. In the pivotal PANORAMA clinical trial, significantly more patients in the 2Q16 and 2Q8 treatment cohorts achieved a ≥2-step improvement in the Diabetic Retinopathy Severity Score from baseline compared with patients in the control group, and significantly fewer patients in the 2 treatment groups had proliferative diabetic retinopathy than in the control group. The approval of aflibercept with 2 dosing options for the treatment of all stages of diabetic retinopathy allows physicians to tailor treatment to the needs of each individual patient.

References

  1. Whitehead M, Wickremasinghe S, Osborne A, et al. Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies. Expert Opin Biol Ther. 2018;18:1257-1270.
  2. Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40:412-418. Errata in: Diabetes Care. 2017;40:809; Diabetes Care. 2017;40:1285.
  3. Wong TY, Cheung CM, Larsen M, et al. Diabetic retinopathy. Nat Rev Dis Primers. 2016;2:16012.
  4. Simó-Servat O, Hernández C, Simó R. Diabetic retinopathy in the context of patients with diabetes. Ophthalmic Res. 2019;24:1-7.
  5. National Institutes of Health, National Eye Institute. Facts about diabetic eye disease. https://nei.nih.gov/health/diabetic/retinopathy. Accessed July 6, 2019.
  6. Regeneron. FDA approves Eylea (aflibercept) injection for diabetic retinopathy. May 13, 2019. https://investor.regeneron.com/news-releases/news-release-­details/fda-approves-eylear-aflibercept-injection-diabetic-retinopathy. Accessed July 5, 2019.
  7. Eylea (aflibercept) injection, for intravitreal use [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals; May 2019.
  8. Drugs.com. Eylea approval history. www.drugs.com/history/eylea.html. Accessed July 5, 2019.
  9. Regeneron. Regeneron announces FDA approval of Eylea (aflibercept) injection for macular edema following central retinal vein occlusion. September 21, 2012. https://investor.regeneron.com/news-releases/news-release-details/regeneron-­announces-fda-approval-eylear-aflibercept-injection. Accessed July 8, 2019.
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