Combination therapy may augment anti-VEGF activity

Combination therapy in AMD has become an important area of research to lower injection burden while maintaining vision gains after monotherapy.

The ability of anti-VEGF therapy to stop fluid accumulation in the macula after neovascularization secondary to age-related macular degeneration has been proven in clinical studies, but no clear answers are yet available on the appropriate endpoint of therapy.

Despite success in treating leakage from new blood vessels, anti-VEGF therapy alone has not been shown to affect regression of newly formed vessels in any significant way. In addition, despite the encouraging results of recent clinical trials in reducing the injection burden involved in AMD therapy with treatment guided by retinal imaging, no as-needed therapy protocols have yet been able to demonstrate equal visual acuity results as seen with monthly injections.

In an effort to reduce the number of required injections while achieving equal visual outcomes, and also to establish a finite treatment paradigm, research in the area of neovascular AMD has moved to the exploration of combination therapy. Although still in its nascent stages, clinical trials have offered a glimpse at some promising add-ons to anti-VEGF therapy that may result in not only the reduction of fluid, but also in the regression of the lesion itself.

Rationale

According to OSN Retina/Vitreous Board Member Peter K. Kaiser, MD, of the Cole Eye Institute, there is little doubt from existing evidence that anti-VEGF therapy is the gold standard for treating AMD; however, the feasibility of continued therapy is untenable.

Peter K. Kaiser

“The problem with anti-VEGF is we are finding out now that more treatments are better than less, so monthly injections appear to be better than less frequent injections, and we’ll know the magnitude of that effect once the results of the CATT study comes out,” Dr. Kaiser said. “Even more important is, irrespective of whether monthly is better than as-needed, we’re finding that in many cases the therapy may need to be continued for an extended period of time.”

Current research in AMD therapy, Dr. Kaiser said, is borrowing from lessons learned from oncology therapy, in which angiogenesis is addressed not by monotherapy, but by attacking the various components of neovascularization from different angles, whether through combinations of chemotherapeutic agents or with pharmacology combined with radiation.

“Similarly, in ophthalmology, we are now trying to attack choroidal neovascularization from several different angles,” he said.

The two phase 3 studies of Lucentis (ranibizumab, Genentech) — ANCHOR and MARINA — showed that anti-VEGF monotherapy was most effective when used as a monthly injection. However, that treatment paradigm did not translate to the real world clinical setting, and so attempts were made, notably with the PrONTO, SAILOR and SUSTAIN studies, to maintain visual acuity results but to reduce the frequency of injections with as-needed dosing based on optical coherence tomography guidance.

Even though visual acuity outcomes in the ANCHOR and MARINA studies were successful at 1 year, Dr. Kaiser said, there was no evidence of new vessel regression despite aggressive therapy, suggesting the need for an additional agent or agents to help effect a return to normal or more normal retinal anatomy.

In another attempt to reduce the shot burden associated with anti-VEGF therapy, researchers in the HORIZON extension study followed patients originally enrolled in either ANCHOR or MARINA with discretionary as-needed therapy. However, according to Pravin U. Dugel, MD, of Retina Consultants of Arizona, visual acuity fell sharply during the 2-year extension after the monthly injection requirement was abandoned.

“What that leads one to conclude is that the treatment that we have is outstanding, but it is outstanding at containing the disease, not getting rid of the disease. As soon as you do anything other than every 4 weeks, you compromise vision because the neovascular membrane never goes away,” Dr. Dugel said.

Pravin U. Dugel

As a result, anti-VEGF monotherapy represents a perplexing paradigm: From a physiologic perspective, anything other than monthly injections compromises visual acuity and thus represents a compromise in care; however, requiring monthly injections becomes unsustainable from a practical and clinical standpoint.

In addition, Dr. Dugel said, the requirement for monthly injections also becomes untenable from an economic standpoint for both the physician and the health care system.

“So now we are at a point where with monotherapy, all evidence points to only one way of doing this, which is to give this on a monthly basis, perhaps ad infinitum,” he said.

“On the other hand, I don’t know of anybody who gives it routinely every 4 weeks in all their patients forever, and the simple reason is that we can’t. We can’t from an economic standpoint because as physicians we simply cannot be economically sound and be profitable by doing this on a monthly basis forever, and we can’t from a health care basis because the system is going to go bankrupt if everybody did that. And patients can’t do that from a logistic standpoint.”

Alternatives

Several combination treatment protocols are being studied, including the DENALI study, which is exploring the use of both normal- and reduced-fluence photodynamic therapy in combination with ranibizumab. According to Dr. Kaiser, who is chairing that study, results should be available in June, “but earlier case reports and case series have shown that doing combination therapy with anti-VEGF and PDT reduces the number of injections and gets pretty good visual results.”

The potential for PDT combination therapy also finds justification in similar studies: The MONT BLANC study, which used standard-fluence PDT and ranibizumab, showed a mean increase of 2.5 letters of visual acuity after a mean 4.8 ranibizumab injections after 1 year, with 31% of patients requiring no additional therapy after baseline.

Another PDT-based study, the RADICAL study, exploring standard, reduced- and very reduced-fluence PDT, ranibizumab and dexamethasone to ameliorate the potential collateral damage of PDT, showed a 6.8 letter gain after a mean three injections over 1 year, with 13% of patients requiring no additional therapy beyond baseline in the standard-fluence PDT group.

“Sine PDT and ranibizumab are already approved, if the DENALI study is positive in June, things could change pretty dramatically,” Dr. Kaiser said.

Radiation

Another combination therapy option for AMD that borrows directly from oncology is the use of radiation with anti-VEGF agents. Newer devices in the later stages of development offer targeted delivery of low-dose radiation that affects chemical factors other than VEGF involved in the angiogenesis cascade.

An epimacular brachytherapy device using a strontium-90 isotope to deliver radiation (NeoVista) is currently being investigated in the phase 3 CABERNET study. In the trial, the combination protocol will be compared with ranibizumab monotherapy in 450 treatment-naïve patients.

A separate trial, the MERITAGE study, may show how the device is applicable in the clinical setting. According to Dr. Dugel, who chaired the study, the combination protocol reduced the frequency of injections by 50% and improved vision in more than 60% of patients at 6 months who had previously unchanged vision despite prior treatment with up to 20 monthly injections.

“This is really the neglected population, quite honestly, because these are the patients that bear the burden of our unsustainable treatment model, and these are also the patients who are the burden for their families, for the health care system and for physicians,” Dr. Dugel said.

The NeoVista device delivers a short burst of beta radiation for approximately 4 minutes from a probe that is held over the target area after a core pars plana vitrectomy is performed. According to Dr. Dugel, the surgical requirement may actually be beneficial, in that it may help oxygenate the retina. The addition of brachytherapy and anti-VEGF therapy culminates in a combination therapy that functions as a “triad of synergistic effects,” Dr. Dugel said.

A radiation platform is also being developed by Oraya (IRay), with phase 3 studies expected to start this summer. The IRay system delivers low dose X-rays in the three sequential beams delivered through the pars plana during a 10-minute in-office procedure.

Although both devices are early in development, they offer the potential to dramatically affect the rapidly dividing endothelial cells that are the hallmark of choroidal neovascularization, according to Dr. Kaiser.

“I’m very excited about both radiation therapies,” Dr. Kaiser said. “I think both, quite frankly, will be quite successful, and the market will decide when to use the particular device. Since one requires surgery and the other doesn’t, we’ll see how the market plays out.”

Therapeutics

Retinal specialists may soon see more pharmacotherapeutic agents that may be used with anti-VEGF therapy to either enhance its activity or to interact with the numerous other factors involved in angiogenesis.

Operating further upstream from anti-VEGF therapy, bevasiranib (Opko Health), which silences the gene that codes VEGF, is being explored both as a monotherapy and as a maintenance therapy after a ranibizumab loading phase.

Two alpha-5-beta-1 integrin agonists — JSM 6427 (Jerini) and volociximab (Ophthotech) — have demonstrated biological activity in quieting non-VEGF components of angiogenesis.

Another compound of interest to researchers is E10030 (Ophthotech), an anti-platelet-derived growth factor (anti-PDGF) aptamer. Anti-PDGF may function to inhibit pericytes, brought on by PDGF after angiogenesis begins, that envelop new vessels, making them resistant to anti-VEGF therapy.

Research is also active in the area of the complement immune system: ARC1905 (Ophthotech) and JPE 1375 (Jerini) target C5 and POT4 (Potentia Pharmaceuticals) targets C3; these proteins may be important in the complement cascade that occurs during macular degeneration. – by Bryan Bechtel

• Pravin U. Dugel, MD, can be reached at Retinal Consultants of Arizona, 1101 E. Missouri Ave., Phoenix, AZ 85014; 602-222-2221; fax: 602-266-2044; email: pdugel@gmail.com. Dr. Dugel is a consultant for NeoVista.
• Peter K. Kaiser, MD, can be reached at Cole Eye Institute, Division of Ophthalmology, A31, 9500 Euclid Ave., Cleveland, OH 44195; 216-444-6702; e-mail: pkkaiser@aol.com. Dr. Kaiser is a consultant for Novartis, Genentech, Oraya and Ophthotech, which have been disclosed and approved by the Conflict of Interest Committee of the Cleveland Clinic.