Going Beyond Anti-VEGF

What new wet AMD treatments on the way?

ANDREW E. MATHIS, PhD, MEDICAL EDITOR

Since the discovery that anti-VEGF agents can play a leading role in the treatment of exudative AMD, much of the research in the area of treatment has focused on Avastin and Lucentis. But researchers are always on the lookout for a novel treatment that may be more effective and incur fewer adverse effects. The final session of the Macula 2009 meeting in New York this year featured 7 presentations addressing, eg, the pros and cons of VEGF blockade, systems of drug delivery other than intravitreal injection, and the current status of the landmark CATT clinical trial.

VEGF AND CYTOKINES

One issue regarding anti-VEGF treatments — being evaluated in the CATT trial — is just how safe treatments such as Avastin and Lucentis really are. Unlike Macugen, Avastin and Lucentis bind to the entire VEGF-A molecule, so some researchers believe that the potential for adverse side effects is greater with the latter 2 drugs.

Ursula Schmidt-Erfurth, MD, wonders whether some amount of VEGF in the eye is necessary for the maintenance and function of the retina. Citing 2 recently published papers that came to opposite conclusions — the first that endogenous VEGF is required for visual function and the second that there is no risk in inhibiting VEGF — Dr. Schmidt-Erfurth, professor and chair of ophthalmology at the University Eye Hospital in Vienna, conducted a study of patients receiving Lucentis for wet AMD with CNV, RVOs, and DME, using cataract patients as a control group; all patients were followed up for 12 months.

Each of the patients in the noncontrol groups was given a single injection of Lucentis, with retreatment given only in cases with subretinal fluid or vision loss. Dr. Schmidt-Erfurth then analyzed the aqueous humour of each patient to detect VEGF levels. She found that there was no VEGF in any of the eyes after 1 month, which is lower than the normal physiological level of VEGF in the eye. In fact, the levels remained at zero through month 2, leading her to conclude that, given the much shorter half-life of Lucentis (9 days), the standard dose of Lucentis may be an overdose.

Dr. Schmidt-Erfurth pointed out that, with the exception of VEGF, which appears elevated in all 3 disease conditions she studied, other cytokines play key roles depending on the retinal disease in question. The only consistent cytokine, VEGF, not only appears in elevated levels in all 3 conditions, but the response to Lucentis is also the same. The key point to take away, she said, was that, because VEGF appears naturally as a free-floating molecule in the intraocular fluids and because Lucentis so successfully suppresses VEGF in the eye, the possibility of long-term effects from Lucentis treatment must be considered.

CATT AT 1 YEAR

Given that a key outcome of the Comparison of AMD Treatments Trials (CATT) will be the comparative efficacy and safety of Avastin vs Lucentis, all eyes are on Daniel F. Martin, MD, chair of the Cole Eye Institute of the Cleveland Clinic and the CATT study chair. While CATT is not yet fully enrolled, Dr. Martin expects full enrollment by fall 2009, with interim data available in 2010.

Thus while Dr. Martin was unable to provide any interim data on the CATT, he did point out positive developments that accompanied the launch of the study. For example, on July 9, 2007, the Revised Medicare Clinical Trial Policy was published. This policy change was in part driven by the CATT and specifically stated that CMS could in fact pay for a drug (Lucentis) in a clinical trial if that drug was otherwise available to Medicare beneficiaries outside of the study. Prior to this policy change, the source of funding for Lucentis was uncertain. This policy change should also benefit future NIH-sponsored clinical trials.

Another key change in the CATT study since its launch concerns some inclusion criteria. Eg, while patients with subretinal hemorrhage >50% of the total lesion were previously excluded, these patients can now be included in the study. This change was made as a result of the increasing use of anti-VEGF agents to treat these patients.

Dr. Martin stated that while much attention has been directed toward the Lucentis/Avastin comparison, the comparison of fixed vs "as-needed" dosing is of equal and 34 possible greater importance. The phase 3 clinical trials proved that Lucentis was effective but not how to best use anti-VEGF therapy. It is hoped that the careful study of as-needed dosing will allow physicians to identify subsets of patients who will most benefit from a less frequent dosing strategy without compromising long-term visual outcomes.

VEGF-TRAP-EYE

Obviously, Avastin, Lucentis, Macugen are not the only treatments for AMD, and others are under investigation. Boston's Jeffrey S. Heier, MD, presented 1-year data from the CLEAR-IT 2 study of VEGF-Trap-Eye, Regeneron's fusion protein that binds to VEGF receptors.

Dr. Heier provided several positive interim data on VEGF-Trap-Eye. The ability of the treatment to prevent vision loss, eg, appears to be very good, Dr. Heier said, and the majority of patients experienced some degree of vision gain. There was also a rapid decline in retinal thickness, which corresponded nicely with the improvement in vision.

But there are fixed-dosing and prn arms in the CLEAR-IT 2 trial. Dr. Heier reported that, in the case of the fixed-dosing arms, patients treated with 4 monthly injections had more robust vision gains than those treated with only 2 quarterly injections. Both groups demonstrated excellent durability over the 10-month prn phase, requiring an average of 2 additional injections.

Moreover, adverse events at year 1 in the CLEAR-IT 2 trial have been rare. Dr. Heier reported a single case of culture-negative endophthalmitis, and less significant adverse events consistent with the kind of complications seen somewhat regularly with intravitreal injections. Also, no patients had serious adverse events who did not have a pre-existing cardiovascular condition, and none were felt to be drug-related.

Dr. Heier reminded his colleagues that, while the CLEAR-IT 2 patients continue in follow-up, VEGF-Trap-Eye is also being tested in 2 phase 3 studies for AMD (VIEW 1 and VIEW 2), as well as a phase 2 study on diabetic macular edema that is comparing 4 doses of the agent against laser, the standard of care for diabetic retinopathy.

NEW IDEAS IN COMBINATION THERAPY

Given that the DME trial about which Dr. Heier spoke involves comparison of laser to a biologic agent and that laser is already being combined with anti-VEGF agents in treating DME, it comes as little surprise that many retinal physicians see combination therapy as the real future of AMD treatment. Peter K. Kaiser, MD, provided the rationale, evidence, and benefits of combination therapy.

Dr. Kaiser, director of the Digital OCT Reading Center at the Cole Eye Institute, stated that, while monthly anti-VEGF therapy seems to be required to effectively treat wet AMD and is emerging as the gold standard, multiple injections carry inherent risks, while prn dosing of anti-VEGF drugs may not have the same efficacy. Like his colleagues, he also pointed out that poorer visual acuity results may occur by stopping anti-VEGF therapy too soon.

Thus, Dr. Kaiser said, it may be necessary to consider agents used in concert with VEGF blockers. He mentioned that a role may exist for combining anti-VEGF agents with photodynamic therapy or radiation therapy, and he pointed to several trials that have been carried out. The FOCUS study, for example, compared photodynamic therapy in combination with Lucentis to PDT alone and found that there was a considerably larger improvement in the combination arm and that lesion size was much smaller after treatment in that arm, which is not seen with anti-VEGF monotherapy. Dr. Kaiser also presented a large case series of patients treated with PDT and Avastin (and sometimes with steroid) that showed a mean improvement in vision of 4.0 letters with 27% of patients not requiring additional treatment over 15 months follow-up. Dr. Kaiser also pointed to the DENALI trial, combining PDT and Lucentis, and its sister trials MONT BLANC and EVEREST, being carried out in Europe and Asia, respectively.

Posing the question of the role of combining anti-VEGF therapies with radiation, Dr. Kaiser pointed to treatments that are under investigation, including the use of isotopes of palladium, strontium, and cobalt. Phase 1 studies of palladium-103 monotherapy, Dr. Kaiser said, were good but "ahead of their time." Clinical trials with strontium in combination with anti-VEGF therapy have been excellent and this treatment is already approved in Europe.

Finally, Dr. Kaiser discussed a future in which physicians will be able to combine other drugs with the anti-VEGF drugs currently available. He noted that it was a matter of not only combining therapies at the same stage of disease, but also applying treatments that target processes that occur both upstream and downstream of the VEGF reaction typical to AMD.

INTERIM 6-MONTH RADICAL RESULTS

Continuing on the issue of combination therapy, Allen C. Ho, MD, spoke about the ongoing RADICAL trial combining reduced-fluence Visudyne and dexamethasone with VEGF inhibition. Reduced-fluence photodynamic therapy is employed in this trial because previous clinical trials suggested that there may be improved safety and efficacy. Dr. Ho, professor of ophthalmology at the Wills Eye Institute in Philadelphia, was careful to remind his colleagues that the 6-month interim data he presented were insufficient to make any strong conclusions.

Dr. Ho said that the arms of the study — 2 arms of triple therapy (half-fluence photodynamic therapy with ranibizumab and dexamethasone; and quarter- fluence photodynamic therapy with ranibizumab and dexamethasone), 1 double therapy (half-fluence photodynamic therapy and ranibizumab) arm, and 1 monotherapy arm of Lucentis (3 injections and then prn injections) only — appear to be safe treatments. There has been a low incidence of adverse effects, including 1 case each of increased IOP, retinal tear, and decreased VA. At 6 months, all study arms demonstrate comparable vision improvement, but it is too early to determine if there will significant differences in efficacy.

Like many other wet AMD trials, the goal of the RADICAL trial is to test whether intravitreal injections of anti-VEGF drugs, here Lucentis, can be given less frequently when given along with other proven therapies. Retreatment frequency is the issue, and Dr. Ho presented a flow chart by which investigators in the RADICAL trial analyze angiographic and OCT results to decide on retreatment. Dr. Ho also indicated that mean cumulative treatment rates were lower in the combination arms when compared to the Lucentis arm, but he again advised that, at 6 months, it is too early to draw conclusions.

CORRELATION BETWEEN ACUITY AND OCT

As most of the studies presented employed OCT to either evaluate patients for retreatment or determine outcomes, the presentation given by David M. Brown, MD, was particularly interesting because it aimed to determine how well correlated VA is with anatomic OCT imaging.

Using the PIER study as his jumping-off point, Dr. Brown noted that there was a very poor correlation between visual acuity and both quantitative OCT (the numerical thickness of the fovea and central retinal volume) and with fluorescein angiography (leakage plus staining). To see whether qualitative assessments of the actual OCT images might provide a better correlation, Dr. Brown graded the OCT images in masked fashion (approximately 6000 images) from the patients in PIER trial looking for evidence of disease activity (intraretinal, subretinal, or sub-RPE leakage). Analysis of this data implies that looking at the actual scans gives a much better correlation with eventual visual outcomes. Those patients who were "dry" on qualitative OCT and remained "dry" on average maintained their vision gains while those with recurrent or persistent fluid on average lost vision over the course of the study. Dr. Brown concluded that this data implies that is important to maintain a "dry" normalized anatomy with whatever treatment strategy is employed. This is best accomplished by either monthly injections or close monitoring with the best available OCT imaging.

To test the hypothesis generated from the PIER work, Dr. Brown then reviewed approximately 4000 qualitative OCT scans from the SAILOR 1 trial. This analysis confirmed the association of better visual acuity outcomes with normalized OCT scans. Interestingly, the patients who responded to treatment anatomically but had multiple recurrent fluid episodes appeared to actually do worse than those patients with either dry retinas or those with chronic fluid. This, he suggested, raises questions about potential visual acuity losses with a true prn treatment strategy. Dr Brown concluded that drying out the retina and keeping it dry appears to be the best strategy for long-term maintenance of visual acuity improvements.

EPIRETINAL BRACHYTHERAPY

The only other presentation at the wet AMD session not to deal primarily with anti-VEGF agents was the presentation by Carl D. Regillo, MD, on epiretinal brachytherapy, ie, the placement of a radioactive agent in very close proximity to its intended target, thus reducing or even eliminating exposure to radiation of healthy tissue.

Dr. Regillo, a retinal specialist at the Wills Eye Institute, talked about NeoVista's investigational device called Epi-Rad 90. The device emits beta radiation, and Dr. Regillo explained that such ionizing radiation delivers to lesions certain antiangionetic, anti-inflammatory, and antifibrotic properties. Stressing how little of the radiation spreads beyond the lesion targeted, Dr. Regillo stated that only 10% of the radioactive dose reached the optic nerve, and a far lower amount was delivered to the lens. Most importantly, he noted, this type of brachytherapy poses little or no risk to the surgeon or staff implanting the device. So far, Dr. Regillo told the audience, no radiation retinopathy has been observed with the Epi-Rad.

Dr. Regillo also discussed the NVI-068 and NVI-111 studies, the latter of which is the combination of brachytherapy with Avastin. In the case of NVI-111, Dr. Regillo reported that at month 18, there was a mean improvement in visual acuity of 6.6 letters, with 73% of patients not requiring retreatment with Avastin beyond the first month. Furthermore, he noted, 37% of the patients in the trial gained 3 lines of vision or more at month 18. Meanwhile, those patients treated only with brachytherapy and without Avastin had less impressive visual acuity results. There was, however, a good drying effect without ongoing anti-VEGF therapy in both studies. Dr. Regillo closed his talk with a brief discussion of the CABERNET trial, a phase 3 trial of the Epi-Rad device.

CONCLUSION

Lest anyone think that FDA approval of Lucentis marked the beginning of the end of wet AMD as the leading cause of vision loss in the United States, the presentationson the condition at the Macula 2009 meeting made it clear that not only do we not know everything there is to know about Lucentis dosing, but we also have yet to discover how well Lucentis (and Avastin) work in combination with both older and emergent therapies. This has stimulated a new push for more effective and durable treatments involving multiple therapeutic approaches to control this difficult disease. Radiation may well emerge to play a key role in treating AMD, and laser cannot be discounted either, even if the Lucentis data seem impressive. RP