Drug therapies moving beyond anti-VEGFs


Pharmacologic activity in the retina realm continues to hold much excitement for new therapies to treat retinal disorders.

Take-home message: Pharmacologic activity-such as combination approaches or gene replacement-holds much excitement for treating retinal disorders.


Editor’s Note: Ophthotech recently announced that the pivotal phase III trials of its anti-platelet-derived growth factor agent (Fovista) failed to achieve the primary endpoint in wet age-related macular degeneration (http://bit.ly/2iJaBkf).

By Michelle Dalton, ELS: Reviewed by Pravin Dugel, MD, Charles C. Wykoff, MD, PhD, and Marco A. Zarbin, MD, PhD

With “everyone” waiting with bated breath for the outcomes of the phase III Fovista study, 2016 may be remembered as the year therapies beyond anti-vascular endothelial growth factor (VEGF) injections to treat retina diseases took center stage, according to specialists.

Ophthotech’s anti-platelet-derived growth factor (PDGF) agent (Fovista) is being investigated in combination with ranibizumab, aflibercept, or bevacizumab for the treatment of neovascular age-related macular degeneration (AMD).

“The phase II study was only 6 months in duration, but it was a large enough trial that it seems reasonable to expect to see a difference between the ranibizumab monotherapy versus the combination therapy cohorts in the phase III studies,” said Marco A. Zarbin, MD, PhD, FACS.

However, if the magnitude of difference in visual outcome between the monotherapy and combination therapy cohorts is small, then “it may not be worth the extra cost and the potential inconvenience of double injections,” cautioned Dr. Zarbin, chairman, Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark. “But if the difference is large, this will be a breakthrough in AMD treatment.”

The “biggest thing by far in retina this year-it’s not even close-is the soon-to-be-released Fovista data,” said Pravin U. Dugel, MD, Retina Consultants of Arizona, Phoenix. Regeneron had some disappointing results with its anti-PDGF co-formulation, but it is too early to discount that category altogether, he said.

New targets are being investigated and some promising results came out this year, he said. For instance, “one of the hottest drugs being looked at right now is Roche/Genentech’s RG7716, which is a bispecific molecule,” he noted.

The other one in the same category is a Regeneron co-formulation, that is also being studied in a phase II trial. Santen and Aerpio are also in this domain, he added.

“The fact that so many great companies are going after the same target . . . validates the target,” said Dr. Dugel, who is also a member of the Ophthalmology Times Editorial Advisory Board. The “big new mechanism” that’s being investigated is the Tie2/angiopoietin (Ang 2) pathway, he said.

Alcon Laboratories’ HAWK trial results will be particularly interesting, said Charles C. Wykoff, MD, PhD, Retina Consultants of Houston and deputy-chairman of ophthalmology, Houston Methodist. In vitro studies found brolucizumab (formerly RTH258 and ESBA1008) binds to all isoforms of VEGF-A including VEGF 165; the molecule is the smallest anti-VEGF to date. It is currently undergoing “a well-powered” phase III trial, he noted.



Beyond VEGFs

“We’re on the cusp,” Dr. Wykoff said. “There are a lot of exciting, ongoing phase II and phase III trials that will come to fruition next year.”

From a pharmacologic perspective, “combination therapies targeting either PDGF or Ang 2 blockade with associated VEGF blockade hold great potential,” he said.

The Ang 2 combination drugs have shown early promise in both AMD and diabetic macular edema (DME), whereas the anti-PDGF drugs are currently only being studied for neovascular AMD, he noted.

“We are hoping for improved outcomes and decreased treatment burden with combination therapy,” Dr. Wykoff said. “For patients, both of these endpoints are important. We’ll have a lot to talk about in 2017, whether the trials are positive or negative.”

With combination therapies, researchers and clinicians will need to determine whether the drugs should be administered simultaneously or in a particular sequence, Dr. Zarbin said.

“It may make more sense to administer Fovista (also known as pegpleranib) first, because the idea underlying therapy with Fovista is that it deprives the endothelial cells of pericyte support in the early stages of blood vessel growth,” he said. “The result is that Fovista exposes the endothelial cells of nascent vessels and makes them more susceptible to VEGF inhibition.”

Simultaneous applications may not optimize the benefit of the enhanced vulnerability of the endothelial cells conferred by Fovista-induced pericyte stripping, he said.

Researchers are still learning about the effects that anti-VEGFs have on the vascular bed of the retina, Dr. Wykoff said.

“It’s possible that blocking Ang2 may have further benefits on the vascular bed,” he said. “The newer pharmacologics in development may prove useful beyond just DME treatment.”

Finally, there are the designed ankyrin repeat proteins (DARPins), a novel class of binding molecules. Allergan’s abicipar pegol “may be more potent than the currently available anti-VEGFs,” Dr. Wykoff said.

Phase II data on the PALM study demonstrated both functional and anatomic improvements comparable with monthly ranibizumab in DME, Dr. Wykoff said. Allergan is enrolling patients in a phase III study for AMD (results expected in 2018) and is expected to move the compound into phase III studies for DME as well.

Topical drops have proven problematic in other disease states because patient adherence is low, but that may not be an issue for patients with AMD. New delivery mechanisms, including Genentech’s sustained-delivery port, “will be a big deal” once results are released, Dr. Zarbin said.

“The poor results seen in many patients with neovascular AMD who have been treated for 5 to 10 years may be due, in part, to a lower- than-desired frequency of injections,” Dr. Zarbin said.

Some studies, such as AURA, demonstrate poor visual outcomes even among patients treated during the first 2 years in “real-world” (versus randomized clinical trial) settings.

“There’s reason to believe that if we could simplify the administration of the medication, we might be able to more closely reproduce the visual results that were achieved in the registration clinical trials, at least during the first couple years of therapy,” he said.

Dr. Dugel said Aerpio’s AKB-9778, a small-molecule Tie-2 activating agent, has potential in DME and diabetic retinopathy, based on early study results indicating its efficacy in blocking vascular leakage and pathologic angiogenesis.

“This compound is delivered subcutaneously, which could prove beneficial for the systemic management as well,” he said.

Genentech’s dry AMD compound, lampilizumab, “was the only one in early phase studies to show a positive result,” Dr. Dugel said. “Acucela’s results were disappointing.”

Acucela is developing emixustat hydrochloride (an RPE65-inhibitor) as a once-daily, orally administered drug. Its SEATTLE study on 508 patients with geographic atrophy secondary to AMD did not meet its primary endpoint of slowing lesion growth compared with placebo.


Gene therapies

Early research into gene-replacement therapies is showing enough promise that the community is taking notice.

“The great thing about these gene-replacement trials is that the FDA has permitted the use of certain viral vectors in patients with degenerative retinal disease,” Dr. Zarbin said.

“That could lead to a simpler regulatory path when you use one of these vectors to deliver therapy,” he added. “This fact may help promote translation of additional gene therapies from the laboratory to the clinic in the next few years.”

Leading the way in this endeavor is Spark Therapeutics, whose phase III pivotal trial on voretigene neparvovec (previously SPK-RPE65) found statistically significant improvement over control subjects in both functional vision and light sensitivity. Spark intends to file for regulatory approval before the end of 2016.

“Being on the verge of gene therapy also means we need to start genotyping people with retinal disease more so that we’re prepared to treat them when the genetic treatments become available,” said Julia A. Haller, MD, ophthalmologist-in-chief, Wills Eye Hospital, Philadelphia. “Hopefully, within the next year, we’ll see some of these gene therapies come to fruition.”

Stem cell therapies, however, are too early stage to be in the same category, noted Dr. Haller, who is also a member of the Ophthalmology Times Editorial Advisory Board.

“There is a lot of interest in how all the advances in cancer pharmacology are going to impact on cancer treatments in the eye,” she said. “Checkpoint inhibitors and CAR-T cells are going to revolutionize treatments for all sorts of cancers, including cancers of the eye.”

Although no new compounds were approved in 2016, the year marked the slow and steady ongoing journey to find better targets, longer-acting compounds, and better efficacy to improve patient outcomes.



Pravin U. Dugel, MD

E: pdugel@gmail.com

Dr. Dugel has financial interest with Alcon Laboratories, Annidis, Novartis, OD/OS, and TrueVision.


Charles C. Wykoff, MD, PhD

E: ccwmd@houstonretina.com

Dr. Wykoff is a consultant for Genentech and has received research supporting grants from the company.


Marco A. Zarbin, MD, PhD

E: zarbin@earthlink.net

Dr. Zarbin Is a paid consultant for companies that include Genentech/Roche, Novartis Pharma AG, Ophthotech, and Coherus Biosciences.



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