February 13, 2017
11 min read

New options under study, but for now anti-VEGF monotherapy remains gold standard for wet AMD

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Anti-VEGF-A therapy will never completely go away for the treatment of neovascular age-related macular degeneration, but new therapies that improve the efficacy and durability of treatment are needed to help bridge the results between clinical data and real-life results for patients.

VEGF-A suppression will not be abandoned, but researchers and ophthalmologists need to find a new way to increase efficacy and the durability of treatment to better serve patients diagnosed with wet AMD, OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, said.

“I do think it’s important to recognize that VEGF-A suppression will never go away. It will always be the crux of our treatment strategy. If the Ophthotech study and the Regeneron study teach us anything, they teach us what a very high hurdle we must overcome to do better than anti-VEGF-A monotherapy. ... I think there is great opportunity to add on another agent for combination therapy that will either get us a greater durability or greater efficacy, and either of those two, but particularly both of those two, will help us close the delta,” Dugel said.

The gap between real-world results and pristine clinical data has never been larger than it is now, according to Pravin U. Dugel, MD.

Image: Dugel PU

A treatment delta exists

The gap between real-world results and pristine clinical data has never been larger than it is now, Dugel said.

When there is such a difference between how patients are treated in a trial and how patients are actually treated in the real world, the treatment gap becomes “bigger and bigger, and that is a dangerous sign for our community and in our field,” Dugel said.

The delta exists in two “silos,” Dugel said, a logistical silo and a physiological silo.

Clinical trials, for instance, suggest patients diagnosed with wet AMD should be given an anti-VEGF-A drug once a month, or every 4 weeks.

“In real life, and we know this in the U.S. from the Medicare database, we are actually treating approximately half as frequently as we should. We know also that as the years go on, the number of injections become less and less and less frequent. This happens for many reasons. Patients drop off, the treatment is not sustainable, and the logistic delta is enormous. We know that for a fact based on real-life data. Almost all the clinical trials are based on a treatment plan that is simply not sustainable,” he said.

The second silo is physiological, Dugel said. When patients are first diagnosed with wet AMD and started on a treatment, they typically have another 15 to 20 years to live.

“But think about this. There is not a single study that I know of that goes past 4 years with anti-VEGF-A monotherapy that improved the patient’s vision above their original baseline. Just think about that. It’s not that the 4 years is not valuable — it certainly is, and anti-VEGF-A monotherapy has changed many, many lives, hundreds of thousands of lives — but it’s important to also understand the limitations. After 4 years, it appears that patients end up where they had begun because vision gradually deteriorates. Patients have many more years to live after that,” he said.


In the phase 2 CAPELLA study, Eylea (aflibercept, Regeneron) with rinucumab was found to not be more beneficial for patients with wet AMD than those who received aflibercept alone. The same was found in two phase 3 clinical studies, OPH1002 and OPH1003, in which patients who received Lucentis (ranibizumab, Genentech) and Fovista (pegpleranib, Ophthotech) anti-PDGF therapy showed no additional benefit compared with patients who underwent ranibizumab monotherapy, according to Ophthotech press releases.

Combination therapies are needed

The treatment delta is the issue ophthalmologists face when they need to treat a patient with wet AMD and why anti-VEGF-A monotherapy cannot be sufficient on its own, Dugel said. Anti-VEGF-A monotherapy has reached its ceiling, so something else in addition is needed for the next improvement in treatment; this is the crux of the argument for a combination therapy strategy, he said.

But, as shown by the outcomes of the recent Regeneron and Ophthotech studies, a combination therapy may be several years away.

The results from these trials were disheartening, Szilárd Kiss, MD, said. These were the two most promising combination therapies tested and were the furthest along in their clinical trials.

Szilárd Kiss

Several therapies show promise

However, there are still several combination therapies under research that have shown promise for the treatment of wet AMD, Kiss said.

“It is disappointing for patients and clinicians, but I think there may still be other pathways to attack, such as the fibrosis pathway, pathways that include neuroprotection and other ways we may be able to combine anti-VEGF therapies. The gains for anti-VEGF therapy were so revolutionary because we had patients going blind before our eyes, and now we’ve gotten rid of that and now the gains are going to be a bit more incremental. There is still plenty of room to improve,” he said.

Ohr Pharmaceutical is enrolling in two prospective multicenter phase 3 trials to evaluate the efficacy of a combination therapy involving squalamine lactate ophthalmic solution 0.2% and ranibizumab for the treatment of wet AMD compared with ranibizumab monotherapy, Kiss said.

Using data from the IMPACT phase 2 study, which demonstrated improvements in best corrected visual acuity and a vision gain of three lines or more in patients who received the combination therapy, the company announced it had reached an agreement with the FDA to evaluate the effects of the combination treatment in two phase 3 studies.

The primary endpoint for the trials will be visual acuity gains at 9 months. In addition, patients will have follow-up visits to measure safety outcomes for 2 years.

Despite the promising data from the IMPACT study, Kiss noted that he does not have high hopes that the combination therapy will prove to be effective in the phase 3 trials.

“I’m skeptical for two reasons. One, drops tend to be more difficult to get to the back of the eye, and two, PDGF was one of the proposed mechanisms by which squalamine may improve results over anti-VEGF therapy, and then PDGF has just failed in two clinical trials,” Kiss said.

Approvals are years away

Unfortunately, the next anti-PDGF therapy will likely not be available soon, and the next potential approval for any drug is likely several years away, OSN Retina/Vitreous Section Editor Andrew A. Moshfeghi, MD, MBA, said.

Andrew A. Moshfeghi

“It’s a little bit disheartening to know that our field isn’t going to change all that much for the next 3 to 5 years. There aren’t even many drugs that are poised to be potentially approvable in that time frame. Even if just one hits, it’s still not going to be a major paradigm shift. We got a little spoiled in the last 10 years, with all of the innovation and all of the success of the drugs we have come to know, Avastin, Lucentis, Eylea, Ozurdex for DME and some of these other drugs. The next 3 to 5 years will be quiet with respect to wet AMD,” he said.

Drug delivery may help

Improved drug delivery may be the next treatment route to have a large impact on wet AMD, and researchers should concentrate their efforts in this area, Judy E. Kim, MD, OSN Retina/Vitreous Board Member, said.


“I believe the next area of advancement that we need to concentrate on with anti-VEGF-A monotherapy is to develop a better sustained drug delivery. We need a way to have these drugs last longer in the eye so that the patients do not have to come in frequently to get the injections. There are several sustained anti-VEGF-A delivery systems being investigated currently, including refillable reservoir implants, encapsulated cell technology, use of nanoparticles and iontophoresis, among others. While many are in the early stages of development, I am hopeful that one or more of these options will reduce the treatment burden while allowing safe and effective treatment of wet AMD and other retinovascular diseases,” she said.

Dugel said Genentech currently has a phase 2 study evaluating a ranibizumab port delivery system. The system is designed for the sustained delivery of ranibizumab for the treatment of wet AMD and could potentially reduce the number of injections and office visits for patients.

Judy E. Kim

The Ophthalmic MicroPump system (Replenish) is another drug delivery system that may one day prove to be effective in treating wet AMD, Dugel said. The system is a small, refillable, implantable ocular drug pump that can be programmed to dispense nanoliter-sized doses of a potential drug at various timepoints for patients, according to the company’s product description.

Inhibiting angiopoietin-2 pathway

Drugs that inhibit the angiopoietin-2 (Ang-2) pathway have also shown promise in treating wet AMD, Moshfeghi said, noting that Regeneron and Bayer are working to develop a combination therapy with aflibercept and the Ang-2 antibody nesvacumab.

A phase 1 clinical study investigating this combination in patients with wet AMD, and separately in patients with diabetic macular edema, found patients had visual acuity and anatomical improvements. Based on this data, Regeneron began enrolling the ONYX trial, a phase 2 clinical trial to specifically evaluate the combination therapy in patients with wet AMD.

Dugel also said this treatment pathway may have the most promise.

“I believe the next big target is the Ang-2, the angiopoietin pathway, and there are several companies targeting this. The idea behind the angiopoietin pathway is to stabilize vessels. We know this is very important in systemic medicine, and we know there is a complementary effect that it has with VEGF inhibition. In that regard, there are a few companies that are targeting this pathway that have encouraging and exciting results. ... In my opinion, the angiopoietin combination pathway is the next most encouraging thing out there,” he said.

Roche is developing a new bispecific antibody, RG7716, for the treatment of wet AMD. Dugel described it as “the most elegantly designed drug for ophthalmology that I’ve seen.”

In a 2016 study published in EMBO Molecular Medicine, Roche researchers noted RG7716 has one antigen-binding arm that binds and neutralizes VEGF-A and a second arm that is an anti-Ang-2 inhibiter.

“It’s a bispecific molecule. Instead of a coformulation, you have one molecule that has two arms. It is put together with a proprietary technology called CrossMAb technology. It has two arms. One arm will inhibit Ang-2, and the other will inhibit VEGF-A. Not only that, the molecule itself has been specifically designed with two mutations. The FC arm, which is the central arm, has been designed with two mutations. One is to increase systemic clearance, and the other is to decrease inflammation. It’s a very elegantly designed molecule that is designed specifically for retina,” Dugel said.

Data from a phase 1 study of the efficacy of RG7716 showed patients who had been diagnosed with wet AMD for 2 or more years had a seven to eight letter improvement in vision after being treated with the drug, despite the average duration of disease being more than 2 years, Dugel said.


Roche is enrolling patients in the phase 2b AVENUE study to evaluate the safety and efficacy of the antibody in participants with subfoveal choroidal neovascularization secondary to wet AMD.

Inhibiting VEGF-C, VEGF-D

Opthea, an Australian-based company, is also developing a new drug, OPT-302, Dugel said. The drug is designed to capture and block VEGF-C and VEGF-D on the receptors VEGFR-2 and VEGFR-3, according to the company website.

This pan-VEGF combination drug inhibits VEGF-C and VEGF-D. Drugs that inhibit VEGF-A tend to upregulate VEGF-C and VEGF-D, Dugel said, so perhaps by inhibiting VEGF-C and VEGF-D, a patient’s resistance to anti-VEGF-A monotherapy may be decreased.

A phase 1 study of OPT-302 as monotherapy and combination therapy with ranibizumab met its primary objectives of demonstrating safety and tolerability, according to a company press release.

The company is currently enrolling patients in a phase 2a dose expansion and is planning to initiate a randomized controlled phase 2b clinical study in wet AMD patients this year.

Another potential anti-VEGF-A product in the pipeline is being developed by Allergan, in partnership with Molecular Partners, Moshfeghi said. Allergan and Molecular Partners are attempting to develop a wet AMD therapy using abicipar, a DARPin-based anti-antiogenic drug. According to Molecular Partners, in phase 2b studies for the treatment of wet AMD, abicipar was shown to provide vision gains that were equal to results with ranibizumab or higher. The data also suggested these benefits may come from abicipar injections every 12 weeks compared with ranibizumab injections every 4 weeks.

This is a novel and promising approach, Moshfeghi said, but like the other treatments in the pipeline, it has not yet been tested long term in wet AMD patients.

“All of them have preliminary human data, which are very exciting, and it seems to indicate a similar if not better drying effect on the macula, a similar if not better visual acuity outcome, and a similar but basically better duration of action than anti-VEGF-A monotherapy. The data is significantly better, but only in a handful of patients tested so far,” Moshfeghi said.

More research

It seems as if the current anti-VEGF-A monotherapy drugs have reached their ceiling for visual acuity and most are equally effective, but there are still other aspects of wet AMD treatment that require further investigation and clinical trials, Kim said.


Reducing the frequency of dosing with a combination therapy or a novel sustained drug delivery system, reducing long-term visual decline due to atrophy or fibrosis, and assessing which drug is best for which patient based on pharmacogenetics or other biomarkers are some areas that need to be further researched, she said.

“Also, less costly biologics with potentially similar safety and efficacy to currently used anti-VEGF-A can be tested. Just as the recent Fovista trial and many previous trials have shown, it is only with clinical trials that we can get the most objective answer rather than treating patients based on personal anecdotes, case series or theoretical benefit,” Kim said.

Despite the slow progress for another wet AMD treatment, Dugel said the current FDA approval system works well. It is a data-driven field with data-driven scientists, and everyone wants to do right by their patients, he said.

“We’re supposed to be data-driven scientists. We’ve all seen instances and have had small trials we’ve participated in where we would have sworn a certain treatment would be the next big thing, but when you actually do the science — the proper large, randomized, prospective dual clinical trials — it doesn’t turn out that way. That is the point. It’s as scientifically important to get a negative result as it is a positive result,” Dugel said. – by Robert Linnehan

Disclosures: Dugel reports he is a consultant for Ophthotech, Novartis, Genentech, Roche and Alcon and a minor shareholder of Ophthotech. Kim reports she receives research support from Carl Zeiss, Notal Vision and Optos and is a member of the Notal Vision advisory board. Kiss reports he is a consultant for Allergan, Alcon, Regeneron, Novartis, Optos and Genentech. Moshfeghi reports he is a consultant for Regeneron, Genentech and Allergan and receives research funding from Regeneron.

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