What’s new in retina pharmacology

The latest offerings include gene therapy, an intravitreal implant and anti-VEGF drugs.

Fifteen years ago, the retina subspecialty saw progress in the treatment of diseases like exudative AMD and macular edema with laser treatment, photodynamic therapy and Macugen (pegaptanib sodium) — introduced by Pfizer, the drug was the first approved by the FDA to treat wet AMD. However, particularly in diseases like AMD, the ability to effectively treat these patients diminished over time, and vision was ultimately lost permanently.

For genetic diseases like retinitis pigmentosa, there were no treatments at all. Instead, patients could expect a steady decline in visual acuity and, ultimately, catastrophic vision loss. Aside from mixed evidence indicating the ability of vitamins to delay progression and the use of low vision adjuncts, patients had little hope.

Today, the retinal treatment landscape is radically different, including changes to the anti-VEGF landscape and the addition of gene therapy for retinal dystrophy patients.

Here are the latest drug offerings available for retinal disease patients.


Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) received FDA approval in December 2017 to treat patients with confirmed biallelic RPE65 mutation-associated retinal dystrophies, which affect the RPE cells then ultimately the photoreceptors of the retina, finally resulting in vision loss. Until Luxturna entered the market, there was no pharmacological treatment available for RPE65-associated retinal degeneration.

Luxturna is a gene therapy administered via an adeno-associated viral vector in the form of a subretinal injection. Patients must still have some viable retinal cells, per the FDA’s recommendation, so patients in the end stages of the disease are not eligible for treatment. In its Phase 3 testing for FDA approval, Luxturna showed improvement of functional vision. “It’s a game changer for those who have this mutation, as the study results have shown very promising improvements in visual function and overall activities of daily living,” says Rishi Singh, MD, of the Cleveland Clinic.

That said, the patient population with these types of inherited retinal dystrophies is small, and the price tag attached to the drug itself is rather large: $425,000 per eye, although the cost is expected to eventually decrease. Where the real promise for Luxturna lies is in the potential for future gene therapies for retina.

“The trials for Luxturna were a proof of concept that has resulted in a plethora of other AAV gene therapy clinical trials for diseases, including choroideremia, Leber’s hereditary optic neuropathy, Stargardt disease, X-linked retinitis pigmentosa and exudative AMD,” says Yasha Modi, MD, assistant clinical professor of ophthalmology at NYU Langone Medical Center.

That the viral vector approach could usher in an era of gene therapies for even the most common retinal diseases, like AMD, means we have yet to see the true potential for this treatment paradigm. “There are also several trials using adeno-associated viruses in the field of AMD, using gene therapy to deliver a protein or additive effect,” says Christine Kay, MD, Vitreoretinal Associates in Gainesville, Fla.

Dr. Singh agrees: “Over time, as gene therapy is better understood, we can imagine a model of a drug that produces portions of the VEGF molecule for inhibition.”

At this writing, two adeno-associated virus-delivered drugs for wet AMD — Regenxbio Inc.’s RGX-314 and Adverum Biotechnologies’ ADVM-022 — are in early phase clinical trials.

Just approved: Beovu

In October 2019, the FDA approved Novartis’ Beovu (brolucizumab), a humanized single-chain antibody fragment developed to treat wet AMD.

This announcement followed the publication of the Phase 3 HAWK and HARRIER studies, which showed noninferiority of brolucizumab to aflibercept in average change in BCVA from baseline to week 48. Aproximately 30% of patients gained at least 15 letters at year one. Also, more than 50% of patients extended to a 12-week treatment interval. Moreover, after 16 weeks of treatment, fewer patients treated with brolucizumab experienced disease activity than those treated with aflibercept.


Retinal physicians have known for some time the importance of steroids in treating inflammatory diseases in the eye, and there is no shortage of sustained-release devices on the market from which they can choose. What might be less clear is which drug to choose, and for which patients. The newest-available option is Yutiq (EyePoint Pharmaceuticals), a fluocinolone acetonide intravitreal implant that delivers 0.18 mg of the drug over 36 months. It is FDA approved for the treatment of noninfectious uveitis.

Despite Yutiq and Bausch + Lomb’s Retisert fluocinolone implant administering the same drug for the same on-label indication, the dosages and release periods are different. Retisert releases 0.59 mg of fluocinolone for 2.5 years, so Yutiq’s dosage is roughly a third that of Retisert and the release period is slightly longer. The biggest difference, however, is that Yutiq does not require surgical implantation. In this regard, Yutiq is more similar to Alimera Science’s Iluvien implant, which is approved for 36 months of release of 0.19 mg of fluocinolone to treat diabetic macular edema (DME).

Dr. Modi adds that the dosage is an important distinction between Yutiq and Retisert. “Certainly, Yutiq is easier to insert as it does not require a surgery,” he says. “Retisert, however, has a longer track record of reducing uveitis recurrences and is a more potent dose. Patients who may benefit from these treatments are patients with unilateral noninfectious disease, those who want to avoid systemic immunosuppression and those who are expecting to be rendered pseudophakic.”

In addition, EyePoint is developing a shorter release version of Yutiq that could allow for a more personalized treatment, says Pravin U. Dugel, managing partner of Retinal Consultants of Arizona and clinical professor at the Roski Eye Institute, USC Keck School of Medicine. “This is a proven technology, and the indication is the difference. I would use it in patients who I know are not infectious and have chronic inflammation due to uveitis.”

In short, Yutiq’s position in the treatment landscape for retina will depend on the indication and the dosage. “It’s about finding an appropriate therapeutic effect for the right patient,” Dr. Modi says. “This is the crux of the difficulty in choosing between these two drugs.”


Now seven years since its FDA approval, Regeneron’s anti-VEGF drug Eylea (aflibercept), originally approved for the treatment of wet AMD, now has approvals for DME, diabetic retinopathy and macular edema due to retinal vein occlusion. The other FDA-approved anti-VEGF drug, Genentech’s Lucentis, is also approved for these four conditions, plus choroidal neovascularization due to high myopia.

The advantage Eylea continues to exercise is its length of efficacy (8 weeks). Over the last seven years, retinal physicians have developed their own preferences for choice of anti-VEGF drug as their numbers of patients have increased and clinical trials have continued to be performed with higher dosages and longer treatment intervals.

“Every patient is different, and it is helpful to have these anti-VEGF drug options, because I do need to occasionally switch among these drugs to enhance efficacy or if a tolerance has developed to one therapy,” says Dr. Kay, adding that some patients may develop an inflammatory response to any of these anti-VEGF drugs. “If a case of sterile inflammation is documented in a patient’s history to one anti-VEGF drug, I will often try to avoid the use of this particular agent in the future.”

Anat Loewenstein, MD, of the Department of Ophthalmology and the Tel Aviv Medical Center, Faculty of Medicine at Tel Aviv University, Israel, says that Eylea has shown particular efficacy in the most advanced cases of AMD. “It has been claimed that, in patients with polypoidal vasculopathy, the drug is particularly effective,” she says, “and it has been shown in the PLANET trial to be as effective as monotherapy when combined with photodynamic therapy.”

“At this point,” Dr. Dugel says, “there are studies being done for higher doses. Where Eylea will fit in with the next generation of anti-VEGF drugs is a question. Currently, it serves as a control for these next generation anti-VEGF-A drug studies. Each company has its own next-generation anti-VEGF-A drug.” Among these drugs is Novartis’ Beovu (brolucizumab), which received FDA approval in October (see page 34).

In the pipeline: Xipere

In February 2019, Clearside Biomedical filed a successful New Drug Application with the FDA for its Xipere triamcinolone acetonide ophthalmic suspension, which Clearside developed for the treatment of macular edema associated with noninfectious uveitis.

At the 2018 AAO meeting, the company presented results of the Phase 3 PEACHTREE trial, in which 68% of patients with vitreous haze experience resolution, in addition to 72% of those with anterior-chamber cell inflammation and 74% of those with anterior-chamber flare.

If all goes well, FDA approval should come next year.


The retina treatment landscape continues to expand, offering therapies for diseases of the retina, both common and rare (see “In the pipeline: Xipere”). As genetic therapies supplement more conventional approaches, we can hopefully expect to see even greater improvements in the care offered to these patients.

If the next 15 years are anything like the last, the sky is the limit. OM