A LOOK AT ANTI-VEGF DRUGS AND WHAT’S ON THE HORIZON

ROUGHLY A decade ago, patients diagnosed with AMD, diabetic macular edema, branch retinal vein occlusion, central retinal vein occlusion and, most recently, proliferative diabetic retinopathy, were almost certain to experience permanent bilateral severe vision loss.

(Although traditional laser treatment is beneficial, it has a small impact on the course of the disease, as well as unwanted side effects, including permanent retinal scarring and decreased peripheral, color and night vision.)

The groundbreaking advent of anti-vascular endothelial growth factor (anti-VEGF) injections has changed this, significantly improving visual prognosis and outcome and, thus, preventing blindness and improving patients’ quality of life.

In this article, I discuss VEGF and the available anti-VEGF agents, so you can educate your patients before you refer them for such injections. (Also, consider those treatments in the pipeline, see “Anti-VEGF Therapies on the Horizon,” p. 32)

VEGF AND ANTI-VEGF DRUGS

VEGF is a protein that plays a key role in the pathogenesis of many blinding retinal conditions, such as those mentioned above. Specifically, it leads to vascular leakage, edema and neovascular growth, all of which can significantly reduce vision. The pathological process results from increased levels of VEGF proteins due to retinal hypoxia or ischemia. VEGF-A, the most potent mediator, results in the formation of new blood vessel growth or angiogenesis and vascular leakage. Targeting the VEGF-A pathway is the cornerstone of anti-VEGF therapies.

The intravitreal administration of anti-VEGF agents restores and improves visual function. Three anti-VEGF drugs are available: (1) ranibizumab (Lucentis, Genentech), (2) bevacizumab (Avastin, Genentech) and (3) aflibercept (Eylea, Regeneron). [Recently, Ophthotec announced that Pegpleranib (Fovista), which was designed to target platelet-derived growth factor, did not meet its primary endpoint of mean change in visual acuity in two pivotal Phase III studies.]

Bevacizumab is an off-label treatment that costs roughly $50 per treatment. The National Institutes of Health’s Comparison of AMD Treatment Trials study reveals it is equivalent to ranibizumab in treating AMD, though causes a higher percentage of serious adverse events, such as heart attacks or strokes vs. its FDA-approved sibling. There is also a risk of vision-threatening infectious endophthalmitis with bevacizumab, due to potential contamination when the drug is repackaged into smaller doses to be used. Yet, in most cases of infection, the source is the surface of the patient’s eye vs. contaminated medication or anything else, according to Ophthalmology. Ranibizumab costs about $2,000 per treatment.

Aflibercept is a VEGF trap drug, as it binds to multiple VEGF receptors, thus, likely requiring less frequent injections. It costs about $1,800 per treatment.

The dosing regimen for all anti-VEGF drugs is monthly injections until VA improves and decreased retinal thickness is observed on OCT. Aflibercept may be dosed every two months. The treat-and-extend dosing regimen, defined as monthly injections until improvement on OCT, is followed by increasing intervals between injections and evaluations, depending on disease activity. This treatment protocol may help reduce the treatment burden and cost associated with fixed monthly or as-needed injection protocols, according to a study in Retina. This was observed in the Aflibercept Treatment with Less-frequent Administration Study, published at the 2016 Association for Research in Vision and Ophthalmology’s Annual Meeting.

Minimal differences in risk exist among all three drugs, according to Ophthalmology. Complications observed:

• Subconjunctival hemorrhage
• Red, irritated eye
• Foreign body sensation
• Tearing
• Cataract
• Cornea problems (abrasions)
• Elevation in eye pressure
• Inflammation (uveitis or vitritis)
• Intraocular infection (endophthalmitis)
• Retinal detachment
• Retina or vitreous bleeding
• Small specks or bubble shapes in vision (can be intermittent or permanent.)

As bevacizumab costs less for the patient vs. ranibizumab, it tends to be a more popular choice. That said, patient assistance programs are available from Genentech (tinyurl.com/retdrug ) and Regeneron (tinyurl.com/eyeret ) to help subsidize costs. Something else to keep in mind: Not all injections may be covered by each insurance carrier, so be sure the patient understands it is his or her responsibility, with the assistance of the eye care provider, to determine coverage.

Anti-VEGF Therapies on the Horizon

The three anti-VEGF drugs that are in the pipeline:

• Abicipar Pegol (Abicipar, Allergan).
  This is a mono-DARpin that inhibits VEGF-A and thus, is being evaluated for the treatment of wet AMD and diabetic macular edema.
  A Phase II trial on DME patients reveals the mean BCVA change from baseline after 28 weeks to 7.1 letters, 4.9 letters and 7.2 letters for abicipar pegol 2mgQ8, abicipar pegol 1mgQ8 and abicipar pegol 2mgQ12, respectively, compared with 9.6 letters for ranibizumab. Recruitment for a Phase III trial is currently in progress.
• ALG-1001 (Luminate, Allegro Ophthalmics).
  This integrin peptide therapy focuses on the integrin receptors in cell signaling and regulation and in the development of new and aberrant blood vessels in vitreoretinal diseases.
  A Phase IIb trial shows the therapy was non-inferior to bevacizumab in the treatment of diabetic macular edema. Specifically, patients who took 1.0mg injections of ALG-1001 once a month for three months and then 12 weeks off achieved a mean BCVA gain of 5.2 letters vs. a mean BCVA gain of 7.0 letters in patients who took 1.25mg of bevacizumab once a month for six months. Also, non-inferiority to bevacizumab was noted in central macular thickness.
• OHR-102 (Squalamine lactate ophthalmic solution, 0.2%, OHR Pharmaceutical, Inc.).
  This is a small molecule that inhibits multiple growth factors and pathways responsible for angiogenesis. It not only works against VEGF, but also platelet-derived growth factor, which is involved in the development of the pericytes that help in the maturation of neovascular vessels, and basic fibroblast growth factor, a cytokine that has angiogenic and inflammatory effects.
  A Phase II study reveals that 40% of those with occult choroidal neovascularization less than 10mm2 who were treated with a combination of OHR-102 and ranibizumab, gained three or more lines of vision vs. 26% of those who took ranibizumab alone.
  Further, those who took the combination treatment gained 11.0 letters vs. 5.7 letters with ranibizumab alone. Phase III clinical trials are in progress.

WHAT CAN YOU DO?

Intravitreal injections of anti-VEGF are now considered the gold standard of therapy in the management of a plethora of retinal conditions. Anti-VEGF treatment modalities are constantly evolving, including a sustained-release treatment. Optimal patient outcomes depend on early diagnosis, prompt referral to the specialist and management of vision-threatening complications.

As optometry is on the forefront of retinal disease,it is imperative that our understanding of how best to use these agents continues to grow, so that we can, in turn, further educate our patients, make informed referrals and management decisions. We are more likely going to see more patients for follow-up care as well, and based on the clinical course of their disease, may need to refer them back to the specialist for subsequent injections. OM

DR. REYNOLDS is an associate professor at the Nova Southeastern University College of Optometry and clinical preceptor/attending in the college’s diabetes and macular clinic. She is a fellow of the Optometric Retina Society and chairperson for the Florida Optometric Association Healthy Eyes Healthy People Committee. Comment at tinyurl.com/OMcomment .