Many questions still remain regarding clinical anti-VEGF regimen, experts say

VIENNA — Anti-VEGF therapy has revolutionized the therapeutic approach to age-related macular degeneration, and multicenter clinical trials have validated the use of specific drugs. However, according to Gisele Soubrane, MD, these studies do not provide answers to all the questions physicians face in daily practice.

The number and frequency of injections, the overall duration of the treatment and the long-term prognosis are still a matter for discussion, and no single trial can give a definitive response, she said at the Euretina Congress here.

After presenting an overview of the principal studies on Lucentis (ranibizumab, Genentech), which Ursula Schmidt-Erfurth, MD, defined as “the only officially approved drug which offers high efficacy and safety,” she concluded that a flexible regimen, with constant monitoring of the effects of the therapy, is probably the best approach. By adopting this individualized approach, a reduction in the number of intravitreal injections can be achieved, with beneficial effects on the patient’s quality of life and a reduction of the public costs involved.

In the MARINA and ANCHOR trials, 80% of the patients who gained lines of vision after the first three monthly injections “did not appear to gain substantial additional benefit by continuation of the monthly treatment for a longer period of time,” Dr. Schmidt-Erfurth said

In the PIER study, the quarterly injections that followed the first three monthly treatments led to an almost equal number of patients who lost, gained or maintained vision. In fact, patients who gained vision were the minority.

“A fixed regimen in quarterly intervals cannot, therefore, be recommended,” she noted.

No specific criteria, such as lesion type or size, baseline vision or disease duration, were identified to predict the level of improvement, which led Dr. Schmidt-Erfurth to conclude that “there are no prognostic factors suggesting more intensive, continued therapy as opposed to less intensive therapy with earlier discontinuation.”

A flexible approach was proposed by the PrONTO study, in which patients, after the usual three monthly injections, received re-treatment only if one of the following changes was observed during the follow-up visits: a loss of five letters in conjunction with fluid in the macula as detected by optical coherence tomography, an increase in OCT central retinal thickness of at least 100 µm, new onset classic choroidal neovascularization, new macular hemorrhage or persistent macular fluid detected by OCT at least 1 month after the previous injection.

With this flexible and customized approach, encouraging visual acuity and OCT results were achieved, and “the number of ranibizumab injections was substantially reduced, from 11 in the other studies to six per year,” Dr. Schmidt-Erfurth said.

Constant monitoring can be a burden, but “since AMD is not a self- limiting disease, a continuous follow-up is mandatory,” she said.

These items appeared originally as daily coverage from the meeting on OSNSuperSite.com. Look for more in-depth coverage of these and other topics in upcoming issues of Ocular Surgery News.

Euretina president says retinal research, treatment have entered new era

José Cunha-Vaz

Retinal research and treatment have made strong progress in recent years, José Cunha-Vaz, MD, PhD, OSN Europe/Asia-Pacific Edition Editorial Board Member president of the European Society of Retinal Specialists, said.

“Patients are actually regaining vision after treatment in diseases like age-related macular degeneration and other retinal pathologies, where the best we could do was preserve, temporarily, residual vision,” Dr. Cunha-Vaz said. “Anti-VEGF therapy, combination therapy and the advancement in research on gene therapy give us all the reasons to be optimistic about diseases that would otherwise progress to loss of vision or blindness.”

Euretina has grown from a niche meeting of a small group of specialists to an international congress with more than 1,500 delegates from 74 countries. Attendance has also grown recently because “the intravitreal injection has opened the door to a lot of new therapies, and even general ophthalmologists are beginning to get interested in the possibilities of these new treatments,” Dr. Cunha-Vaz said.

Surgeon explains options for sustained intraocular drug delivery

Intravitreal injections are a long-established, effective form of drug delivery into the eye. However, the need for frequent injections is a concern. Longer-term drug delivery systems may represent a better, less-invasive approach to the treatment of macular edema, according to Baruch Kuppermann, MD.

The Bausch & Lomb Retisert reservoir-style implant for sustained delivery of fluocinolone has obtained U.S. Food and Drug Administration approval for the treatment of uveitis. Dr. Kuppermann said the benefits of the implant are remarkable.

The implant requires a surgical procedure with a 3.5-mm pars plana incision. The device is designed to last for about 1,000 days, delivering a total of 0.5 mg of the substance.

The same implant was also tested for diabetic macular edema, but although benefits were shown, safety concerns were raised by a high rate of increased IOP and cataract.

“The low 0.5-mg dose used against placebo surprised us for how potent the effect was, which confirms the efficacy of this way of delivering anti-inflammatory agents. However, glaucoma occurred in almost 50% of the cases, and cataract was practically ubiquitous. The company therefore decided to limit the indications to uveitis,” Dr. Kuppermann said.

The Alimera Medidur implant also releases fluocinolone but has the advantage of being delivered through a 25-gauge injection. This allows implantation in an office setting.

“Once injected, the implant floats freely into the vitreous cavity,” Dr. Kuppermann explained.

Two release rates — 0.5 mg and 0.2 mg — are available. Duration in both cases is 1 year. “Phase 3 trials on [diabetic macular edema] are currently ongoing. Up to now, the safety and efficacy profile seems promising,” he noted.

The Posurdex biodegradable dexamethasone implant (Allergan) is a different concept. It is not a reservoir but a biodegradable implant in which the drug is incorporated into a polymer matrix. As the polymer degrades, the drug is released. The first model required surgical implantation in the operating room, but a new version, which is currently used in phase 3 trials, uses an injection process with no surgical incision and can be used in an office setting. Once inserted, the implant floats into the eye.

“Data from a large study on patients with persistent macular edema that failed all other therapies showed a remarkable gain of three or more [visual acuity] lines at 3 and 6 months,” Dr. Kuppermann said.

The SurModics I-vation implant is a helical coil containing triamcinolone within a polymer coating.

It is implanted through a 25-gauge needle, and it is self-anchoring within the sclera, so it may be able to be implanted in a nonsurgical setting. Duration is about 18 months. A multicenter trial on this implant is under way in patients with DME.

“In conclusion, we have two fundamental approaches and philosophies with regard to ocular drug delivery. On one hand, we have the longer-acting reservoir implants, which have good long-term control of the disease but a potential for side effects. Even low levels of chronic bathing of the eye with steroids may be associated with increased risk for developing cataract and glaucoma,” Dr. Kuppermann said.

“The other approach, particularly that of the new Allergan-Oculex Posurdex model, provides shorter-acting biodegradable inserts that potentially expose the eye to a lower risk of complications and may provide a sufficiently good control of the disease,” he said. “Potential recrudescence can be re-treated, thus minimizing unnecessary drug exposure.”

“It is possible that each approach might have preferential uses in different diseases with different drugs,” Dr. Kuppermann said.

Three-step program may have better success for PVR after retinal detachment

Proliferative vitreoretinopathy after retinal detachment is better managed by a three-step program of operations in the most severe cases, according to one surgeon.

“Unfortunately, PVR can be quite a frequent complication of retinal detachment if the access to health care is delayed. The rate varies from 5% when retinal detachment is detected promptly to as much as 53% when this is delayed for 2 or more months,” Tom H. Williamson, MD, said.

He emphasized that the key to successful PVR surgery is timing. The temptation is to achieve a completely flat retina as soon as possible, for example by early relaxing retinectomy.

“Operating on an eye with active PVR can result in a proliferation of membrane formation because the surgical procedure increases the stimuli for PVR,” Dr. Williamson said. “PVR must be in a quiescent state before retinectomy is performed, but this requires at least partial reattachment of most of the retina to minimize the release of cytokines and growth hormones from breakdown of the blood-retinal barrier.”

For this reason, a three-step program was designed to allow reattachment of the majority of the retina with consequent reduction of PVR stimuli, delaying retinectomy for 3 to 6 months later before proceeding to silicone oil removal.

“At the first operation, vitrectomy is performed and the eye is filled with silicone oil, which in most circumstances flattens two-thirds of the retina, leaving the inferior retina detached because of its shortening. With the macula in place, the retina is left for 3 to 6 months for the PVR process to become quiescent,” Dr. Williamson said.

At a second operation, the inferior retina is cut as far peripherally as possible to perform a relaxing retinectomy. Diathermy to the visible peripheral retinal blood vessels is applied to avoid bleeding. The retina is cut with vertical cutting scissors to fashion the retinectomy, cutting through the diathermy points. The vitreous cutter is used to remove the redundant anterior retina, and radial cuts are performed in case of retinal folds. Silicone oil is inserted, and laser retinopexy is performed.

At a third stage, after 3 to 6 months, silicone oil is removed and the retina is inspected.

In a study including 27 patients with PVR, 25 (93%) achieved a flat retina, with removal of the silicone oil in 81% of the cases.

Success rate is usually low in patients with PVR, approximately 62% to 65%, despite the variety of methods used.

“This program appears to provide a high chance of reattached retina and silicone oil removal,” Dr. Williamson said. “Visual acuity remains low, but this reflects the damage to the macula from the PVR process and the retinal detachment.”

Treatment combines low-dose radiation, anti-VEGF therapy for neovascular AMD

A new method of selective epiretinal brachytherapy combined with anti-VEGF therapy may be a promising treatment approach for patients with neovascular age-related macular degeneration.

Eugene de Juan

“Radiation has been used for some time in the treatment of ocular neovascularization. It is an interesting option because it attacks several of the important components of the disease. It is antiangiogenic but also anti-inflammatory, which may have an important role in the recurrence of the disease, and also antifibrotic,” Eugene de Juan, MD, said. “Importantly, it can work synergistically with other therapeutic approaches. Avastin (bevacizumab, Genentech) and radiation have shown synergism in colon cancer.”

Studies have shown moderate effects on stabilization of vision — fairly prolonged over a couple of years but modest in terms of visual gain. From a safety standpoint, a low rate of radiation retinopathy was found, he noted.

The new retinal brachytherapy device used at the Doheny Eye Institute in Los Angeles delivers a single intraocular treatment with 24 Gy beta radiation, utilizing a strontium-90 isotope. The procedure is carried out under local anesthesia. Vitrectomy is performed, and a probe is placed into the vitreous cavity. Through this, a small radiation source is placed over the neovascular area and left in place for 3 to 4 minutes.

“The radiations are directed to the edge of the lesion, where they have a peak of power that fades toward the periphery. The exposure of surgeons and assistants to radiation is negligible,” Dr. de Juan said.

Unlike other brachytherapy methods, this device has a significant impact on vision, he said.

Radiation alone resulted in visual stability in about 90% of the patients over 2 years. About 50% of the patients gained one or more letters of vision, and 17% gained more than 15 letters.

Cataract was a common complication, as is expected in procedures involving vitrectomy, and a few other small complications were reported.

“Now, roughly 200 patients have been treated, many have more than 2 years of follow-up and no case of radiation retinopathy has been reported,” Dr. de Juan said.

He said he thinks this is due to the small radiation dose and to the focal character of the radiation delivered.

The brachytherapy treatment has also been found to work synergistically with anti-VEGF therapy. In a pilot study, a single radiation treatment was combined with two injections of bevacizumab. One of the injections was given immediately after the radiation procedure and the second one 30 days later.

As a result, a mean improvement of 10 letters was reported at 12 months. Seventy percent of patients improved or maintained their visual acuity, and 39% gained three or more letters.

One year after treatment, no adverse events associated with the exposure to radiation were found.

Dr. de Juan said that the advantage of this approach over anti-VEGF therapy alone is the fact that the radiation treatment is delivered only one time and the number of intravitreal injections is significantly reduced.

“This makes the treatment more cost-effective and certainly more advantageous for the patient’s quality of life,” he said.

Off-label use of bevacizumab raises medical and ethical concerns in Europe

Currently available safety and efficacy data do not provide sufficient evidence to justify the off-label use of bevacizumab in the treatment of age-related macular degeneration, according to a specialist.

“The major portion of published data derives from small and short-term studies,” Paolo Lanzetta, MD, said. In addition, “the availability of registered drugs such as ranibizumab and pegaptanib (Macugen, OSI/Pfizer) raises further ethical concerns.”

Despite the initial assumption that full-length antibodies would not pass across the retina, several studies demonstrated that bevacizumab is able to penetrate the retina after intravitreal injection, and a promising efficacy profile was proven for neovascular AMD. Also, in clinical practice, the incidence of local side effects did not seem to differ from other intraocular drugs. Electrophysiological studies showed no side effects on the retina, and in vitro and in vivo experiments excluded short-term negative effects on ocular cells and histological structures.

“However, a mitochondrial disruption in the inner layers of photoreceptors and apoptosis has been reported after high doses of bevacizumab administration in rabbit eyes. One reported side effect is the occurrence of retinal pigment epithelium tears (5% to 10%), usually subsequent to large and hemorrhagic pigment epithelium detachment. Rapid fluid resolution or contraction of the fibrous tissue has been suggested as potential causes,” Dr. Lanzetta said.

In addition, in the absence of long-term randomized controlled trials, safety concerns with systemic side effects are not yet entirely dispelled, he said. Bevacizumab accesses the systemic circulation, and this may explain the biological effects observed in the contralateral eye and the significantly elevated blood pressure levels reported in some patients after intravitreal injection, Dr. Lanzetta said. However, a recent 1-year prospective study of 60 eyes reported no ocular or systemic side effects.

The lack of coherent, evidence-based data makes the use of bevacizumab professionally hazardous and an ethically questionable practice, he said.

“The off-label use of a product within the medical profession is not illegal in any part of the world, but physicians have the responsibility to base its use on firm scientific rationale and medical evidence,” he said.

European Vision Institute creates basis for common standards in multicenter clinical trials

The EVI.CT.SE network of clinical trial centers, founded in 2003, is increasingly becoming a major reference point for vision scientists, research institutes, ophthalmic industries and patient organizations, Dr. José Cunha-Vaz said.

The EVI.CT.SE organization, which stands for European Vision Institute, Clinical Trials, Sites of Excellence, is principally aimed at creating the basis for common standards in the performance of multicenter clinical trials and in daily eye care delivery. Clinical trial site members must fulfill the requirements of the network, namely by having adequate infrastructures, equipment and qualified staff and following the European and international directives for clinical trial research. The network has 45 clinical site members; 28 are already certified and 17 are in the certification process. Twenty more centers are candidates for membership.

The EVI.CT.SE network is a crucial step forward in providing patients with the best standards of care in terms of safety and efficacy.

“In the era of evidence-based medicine, it is mandatory to fund our practice on the validated and reliable results coming from multicenter, randomized, controlled clinical trials,” Dr. Cunha-Vaz said.

By improving the quality and efficiency of clinical research in Europe and facilitating international clinical trials, the EVI.CT.SE will increase standards of research, care and public health services and will increase the competitiveness of Europe, he noted.

“We hope [for] some kind of support from the European Union, which has recently included sense organ disorders in the list of priorities in its 2008-2013 public health program,” Dr. Cunha-Vaz said.

Surgeon: Vitrectomy with triamcinolone and ILM peeling best treatment for CME

Despite many studies, cystoid macular edema remains an unsolved problem after 40 years of evidence-based treatment.

According to Peter Wiedemann, MD, the most effective approach is vitrectomy with internal limiting membrane (ILM) peeling. Triamcinolone is an essential tool to the success of the procedure.

“The rationale for vitrectomy is that it conveys oxygen from the ciliary body to the retina. In diabetes, the vitreous is very adherent to the retina, and a spontaneous reabsorption of the edema occurs in more than 25% of the cases where vitreous detaches,” Dr. Wiedemann said.

Laser photocoagulation also brings oxygen to the retina, but of all the treatments, it is the most destructive, with negative effects on retinal thickness and vision.

Dr. Wiedemann emphasized that in performing vitrectomy for CME, triamcinolone is useful. Macular edema may be caused by cytotoxic changes or, for vasogenic cases, by high blood pressure.

“Triamcinolone inhibits the inflammatory mediators and the production of VEGF and opens the channels specifically to remove calcium and water from the cells. So, it works against cytotoxic edema. Studies have shown that it is also more effective than anti-VEGF,” he said.

The anti-edematous effect is prolonged with repeated treatments.

As a surgical tool during vitrectomy, triamcinolone is useful in providing better visualization of the transparent vitreous and therefore allows easier, better and more complete removal of the posterior hyaloid from the ILM, he said.

“Residual collagen fibers and cellular components tend to remain on the ILM if you don’t use it,” Dr. Wiedemann noted.

As far as ILM peeling is concerned, there is no uniform consent on its benefits and its impact on foveal thickness and visual acuity.

“I believe that this is due to the method of ILM removal. There are different techniques, and different results are correlated to them,” he noted.

In his opinion, ILM peeling is useful in diabetic CME.

Dr. Wiedemann said that his approach is basic treatment with glycemia and blood pressure control, no laser, vitrectomy with triamcinolone and ILM peeling with a short exposure time, and no yellow light.

“The benefits of additional anti-VEGF and additional triamcinolone should be assessed in the future, and randomized trials should be performed to find the best treatment solution and provide surgeons with uniform, validated guidelines,” he noted.

Vertical OCT can reduce face-down positioning in most macular hole patients

Unnecessarily long face-down positioning after macular hole surgery can be avoided by the use of a new vertical OCT technology, according to Claus Eckardt, MD.

“In most of the patients, the hole is fully closed within 24 hours, but examining the macula while the air is still in the eye is just not possible. The beam strikes the bubble tangentially, preventing visualization,” he said. A solution would be to have the eye rotated, and this is only possible with the patient facing down.

The Topcon OCT has the capability for 90% angle rotation. In Dr. Eckardt’s clinic, the device is mounted on a mobile armature, which allows examination from below with the patient in the prone position.

“We can visit the patient 24 hours postoperatively, and we have seen that the number of fully closed holes at this early time is much higher than expected. On the other hand, in most cases, if the hole is not closed at day 1, it will still not be at day 3,” he said.

A series of 33 eyes was prospectively examined to establish OCT-based duration of face-down positioning. At 24 hours, 54% of the eyes showed a closed macular hole. Another series of 100 eyes showed that very large holes are closed within 1 day.

Dr. Eckardt said that simple air tamponade can result in 91% hole closure and allows vertical OCT at 24 hours. Longer-lasting gases are not necessary.

“When you tell your patients that, most likely, they will not have to stay in the prone position for longer than 1 day, they feel a lot better and more motivated to follow the surgeon’s instructions. After you have examined them at day 1, you can make an OCT-based decision on whether to prolong the duration, but all unnecessary cases will be avoided,” he said.

Cell-based therapies may have a role in treating retinal diseases

Cell-based therapies such as retinal pigment epithelium transplantation offer a viable alternative to treat retinal degenerative diseases such as age-related macular degeneration, and the therapies are expected to improve in the coming years, according to a surgeon.

“Retinal pigment epithelial cells play a central role in maintaining visual function of the retina. A healthy RPE maintains an equilibrium between VEGF inhibition and [pigment epithelium-derived factor] production, among many other functions. Therefore, cell-derived therapies have a logical application in degenerative retinal disorders, and clinical and experimental results justify further research in this field,” Susanne Binder, MD, said.

In a prospective, randomized study, two techniques of autologous RPE transplantation were compared: RPE choroid sheet and RPE suspension. The patients enrolled in the study were affected by neovascular AMD with progressive visual loss. For various reasons, they were unsuitable to receive treatments involving laser, photodynamic therapy or anti-VEGF intravitreal injection.

In both treatment groups, visual acuity improved or remained stable, and results were comparable between groups. RPE flap vascularization was visible on indocyanine green angiography, and OCT showed decrease of central retinal thickness. No recurrences occurred in either group during the follow-up period.

Good results reported for dexamethasone biodegradable implant

George Williams

Patients with persistent diabetic macular edema can benefit from sustained delivery of dexamethasone through a drug delivery implant, according to a study.

“Posurdex (Allergan) is a biodegradable implant. The drug is incorporated into a polymer matrix, which gradually breaks down into inert compounds, releasing the active agent over a long period of time,” George Williams, MD, said.

A total of 315 patients with persistent macular edema due to a variety of causes were randomized in a phase 2 prospective multicenter study to no treatment or treatment with a 350 µm or 700 µm dexamethasone drug delivery system.

“The Posurdex implant showed significant efficacy in terms of visual gain in all [macular edema] patients, particularly at the higher dose of 700 µm, both at day 90 and day 180. A gain of 10 or more letters was achieved in about 35% of the patients, and a gain of 15 or more letters in 18% of the patients. In the subgroup of patients with diabetic macular edema, the results were consistent with those of the overall patient population,” Dr. Williams said.

Retinal thickness, measured by OCT, was significantly reduced, three times greater with the 700 µm dosage than with the 350 µm dosage.

Increased IOP was reported in 14.5% of the patients in the 350 µm group and in 9.4% of the 700 µm group.

There were two cases of extramacular traction retinal detachments in diabetic patients, one in the study eye of a patient in the 350 µm group and one in the nonstudy eye of a patient in the observation group. Neither case was considered by the investigators to be related to treatment.

There was no difference between the groups in the incidence of cataract.

“A higher incidence of vitreous hemorrhage was observed in the treatment group,” Dr. Williams said. “The investigators considered it likely to be due to the surgical procedure rather than to the study medication.”

No cases of endophthalmitis were reported.

Phase 2b and phase 3 of the study are currently under way with the new version of the Posurdex, implanted with an applicator that produces a small, self-sealing wound.

A note from the editors:

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