RPS 2011: Viva Las Vegas

An overview of the 7th Retinal Physician symposium.

Sumit Sharma, MD • Peter K. Kaiser, MD

The 7th annual Retinal Physician Symposium was held at the Palazzo Hotel in Las Vegas from February 23 to 26, 2011, with a focus on current and future treatment strategies in medical and surgical retina. Retina specialists and general ophthalmologists attended the four-day meeting, the goal of which was to allow attendees to interact with each speaker during the interactive question and answer sessions after each presentation, moderated by Jason S. Slakter, MD and Peter K. Kaiser, MD. If you have never been to a RPS meeting, this is the most valuable time, as the roaming moderators get everyone involved in the discussion, which are often longer than the presentations.

WEDNESDAY'S SESSIONS: DRUG DEVELOPMENT

Wednesday evening's opening session focused on the drug-development process. The session was moderated by Quinton Oswald, the CEO of SARcode, and Emmett Cunningham, MD. Jay Chiang, PhD, from McKinsey discussed the process of drug development from research to NDA filing. This presentation was followed by a panel discussion moderated by Dr. Cunningham on the early stages of drug development, including a venture capitalist specializing in health care and the CEOs of several early-stage companies: Oraya, LPath and iCo Therapeutics.

Attendees learned about the road from drug discovery to phase 1 clinical trials, including how to fund this stage. Wednesday's session concluded with a late-stage development panel consisting of the CEOs or top ophthalmology executives of several late-stage companies, including Genentech, Regeneron, Alimera and Neovista, that was moderated by Mr. Oswald. The session concentrated on the hurdles late-stage companies face in bringing drugs to the market, especially in light of bevacizumab and the vortex this drug has caused in funding future drug development. A unique aspect of this session was the interaction between the physicians, industry and investment community. Each side was able to see the views of the others in an open forum. Following the symposium, there was a cocktail reception where attendees got to mingle with the faculty and peers.

THURSDAY'S SESSIONS

• Age-related Macular Degeneration. Thursday's session focused on everything AMD. The morning session began with a discussion by K. Bailey Freund, MD, on whether we need a new classification system for CNV. He discussed the current classification system and showed how OCT has given us new evidence that we may need a new system. The Q&A session that followed discussed how these findings may alter treatment decisions for AMD patients.
• Combination Therapies. Peter Kaiser, MD, presented the results of the RADICAL and SUMMIT trials testing the combination of verteporfin photodynamic therapy and ranibizumab. The rationale for combination therapy is that anti-VEGF does not cause regression of abnormal blood vessels while PDT does cause regression of the vessels and may result in long-term control of leakage with less frequent injections than the current gold standard—monthly injections.

The RADICAL study examined quarter-fluence PDT and half-fluence PDT with ranibizumab prn and dexamethasone (triple therapy) vs prn ranibizumab monotherapy in patients with wet AMD and found no difference in visual acuity after 12 months, though there was a lower retreatment rate with triple therapy.

The MONT BLANC study examined prn ranibizumab vs PDT with ranibizumab prn in patients with wet AMD and met its primary outcome, ie, noninferiority between groups in terms of visual acuity. However, it did not show any difference in number of treatments, despite one-third of the patients getting combination therapy not needing additional treatment after loading treatment.

The DENALI study examined standard-fluence PDT with ranibizumab prn vs half-fluence PDT with ranibizumab prn vs monthly ranibizumab alone in wet AMD. Though the study did not meet the noninferiority margin, with monthly ranibizumab not noninferior to the combination groups, the number of treatments in the combination groups was considerably less.

Finally, the EVEREST study examined PDT alone vs ranibizumab prn vs PDT plus ranibizumab prn for polypoidal choroidal vasculopathy and found that the two PDT arms met the primary endpoint of polyp regression significantly better than ranibizumab alone, while VA was similar among all three. All three SUMMIT studies showed that combination therapy was safe.

The take-home point from these trials: combination therapy with PDT and ranibizumab is not recommended as a primary therapy for wet AMD but should be considered if the patient is willing to lose some vision in exchange for a decrease in treatment burden. In contrast, PDT should be part of the primary treatment regimen for PCV.

Pravin U. Dugel, MD, and Darius Moshfeghi, MD, then presented the results of two different approaches using low-dose, focused radiation combined with anti-VEGF to treat CNV in AMD patients. Dr. Dugel presented the results from the MERITAGE trial using epimacular brachytherapy and anti-VEGF after pars plana vitrectomy in patients who were failing anti-VEGF injections before enrollment. Combination therapy with brachytherapy was found to be safe, with no radiation retinopathy reported, it cut progression of vision loss by 80%, and it dramatically decreased injection frequency, with almost 50% of difficult-to-treat patients showing an increase in VA.

Dr. Moshfeghi presented results from a phase 1 trial of the IRay external beam radiotherapy device combined with ranibizumab, showing that the combination treatment was safe, with no radiation retinopathy reported, as well as effective in reducing the need for additional ranibizumab injections. This presentation was followed by a discussion of the pros and cons of each approach, with both devices offering a much more precise dose of radiation only to the tissue of interest, with the brachytherapy approach having associated surgical risks. The external device is easier to administer with no surgical risks/costs but may not be as widespread because the device itself will be very expensive.

Jeffrey Heier, MD, and Victor Chong, MD, presented the results from the pivotal phase 3 studies of VEGF Trap-Eye (Regeneron) in patients with wet AMD: VIEW 1 and VIEW 2. VIEW 1 was based at 188 sites in the United States and Canada and VIEW 2 at 190 sites in Europe, Asia, Australia and South America. Both trials enrolled approximately 1,200 participants. VEGF Trap-Eye should theoretically have a longer biological activity in the eye owing to its dramatically higher affinity for VEGF than ranibizumab, allowing it to be dosed less frequently. The primary endpoint was statistical noninferiority in the proportion of patients who maintained (or improved) VA over 52 weeks compared to ranibizumab. Both trials showed that all doses of VEGF Trap-Eye, including the group dosed every two months after a loading phase, successfully met the primary endpoint compared to the current standard of care, ranibizumab dosed monthly.

Daniel Martin, MD, gave an update on the Comparison of AMD Treatments Trials. CATT has four arms comparing monthly to as-needed ranibizumab and bevacizumab, and has completed the primary one-year endpoint. Dr. Martin gave an overview of the designs of various studies going on around the world comparing ranibizumab to bevacizumab given in various dosing intervals with different retreatment criteria. Results of CATT have not yet been released pending publication of the study results, but Dr. Martin plans to present the results at this year's ARVO annual meeting in Fort Lauderdale in May.

A heated discussion followed, centering on what audience members thought the results of the trial would show and how those results would impact clinical practice in the management of neovascular AMD. In addition, extensive discussion surrounded how VEGF Trap would fit into our armamentarium after the CATT results.

In his second presentation, Dr. Freund discussed elevated IOP after anti-VEGF injections. This phenomenon was seen in multiple reports and also in a post hoc analysis of the MARINA and ANCHOR data. Most reports show that there is an immediate postinjection IOP spike to >30 mm Hg, followed by a reduction to <30 mm Hg after 20 minutes. There is a strong correlation between the number of injections given and the risk of late sustained IOP elevation. Multiple theories have been proposed, but there is no strong evidence supporting any theory at this time.

Dr. Slakter then presented case reports showing how to manage patients who are nonresponders to anti-VEGF. He described five categories of nonresponders and how he deals with each: patients who need frequent retreatment or treatment more often than every four weeks, patients who stay fluid-free for a long time then rebound, patients who have no response to treatment due to misdiagnosis, patients who get worse after treatment, and patients who develop a hemorrhage after treatment. This presentation was followed by a discussion of how different specialists deal with anti-VEGF nonresponders in their own practices.

• Alternative Treatments for AMD. Dr. Heier returned to discuss other anti-VEGF drugs in various stages of development or clinical trials. KH902 (KangHong) is a fully human fusion protein that functions as a VEGF decoy receptor and is entering phase 2 trials in China. It is similar to VEGF Trap but includes another domain that theoretically helps with penetration. Pazopanib (GlaxoSmithKline) is a topical tyrosine kinase inhibitor of multiple receptors involved in the VEGF pathway, including VEGF-1/2/3, platelet derived growth factor α/ß (PDGF) and cKit, and it is being tested in a phase 2 trial. Palomid 529 (Paloma) is a TORC1/2 inhibitor that selectively inhibits aberrant angiogenesis but allows normal angiogenesis to occur.

Dr. Heier also gave an overview of gene therapy for retinal diseases and described AAV2 sFlt01 (Genzyme), a chimeric VEGF-binding molecule delivered by an adeno-associated viral vector (AAV). The AAV vector is taken up by perifoveal ganglion cells, which then produce sFlt01, the soluble form of the VEGF receptor, which binds extracellular VEGF. AAV2 sFlt01 is entering clinical trials at this time.

Angiogenesis is a very complex pathway, and so far all of the approved treatments block VEGF in the extracellular space or at the receptor level. David Boyer, MD, discussed treatment options that do not involve the VEGF pathway. These options included the complement pathway, RNA interference, integrins, platelet-derived growth factor, nicotinic Ach receptor antagonism, and hypoxia inducible factor inhibition. Blocking some of these pathways may also help prevent fibrosis and scarring because these processes are also involved in those pathways, in addition to angiogenesis. The discussion focused on how the future will involve tailoring a combination of therapies to the patient's needs.

David Chow, MD, discussed the roles of genetics, inflammation and complement in the natural history of AMD. Many genetic studies have linked complement to the development of AMD, with the most important identified between complement factor H and ARMS2. Dr. Chow then discussed the role of genetic testing in AMD, describing patients in whom testing would be warranted: children and siblings of affected patients and affected patients (to check for risk of progression of dry AMD and/or predict response to therapy and prior to selecting a multifocal IOL). After his presentation, there was discussion of the social issues raised by genetic testing.

• Dry AMD. The focus then shifted to dry AMD, with Dr. Slakter discussing treatment modalities aimed at modulating the complement cascade to limit progression of dry AMD. Intravitreal injections of POT-4 (Potentia/Alcon) inhibit the conversion of C3 to C3b; POT-4 is starting phase 2 trials. Eculizumab (Soliris, Alexion) is a monoclonal antibody against C5 approved to treat paroxysmal nocturnal hemoglobinuria and now being examined by intravenous injection for preventing progression of geographic atrophy. ARC 1905 (Ophthotech) is a specific aptamer that also works on C5, preventing the formation of C5a and C5b. It is in phase 2 trials.

For the final talk of the day, Dr. Boyer took the stage again to describe several therapies aimed at visual-cycle modulation and neuroprotection to prevent progression of dry AMD. Ciliary neurotrophic factor using encapsulated cell technology (Neurotech) has completed phase 2 testing. The encapsulated cell technology is an intravitreal implant containing human RPE cells that have been genetically modified to express CNTF through a semipermeable polymer outer membrane. RPE cells express a constant amount of CNTF into the vitreous cavity, which is neuroprotective for the RPE into the vitreous cavity. In early studies, there was a dose-dependent increase in retinal thickness with a trend toward an emerging visual acuity benefit.

A sustained-release brimonidine implant (Allergan) is also being studied to see whether there is a neuroprotective effect in dry AMD. Tandospirone (Alcon) is a topical selective serotonin agonist that increases resistance to oxidative stress and limits apoptosis. It is in phase 2 testing.

Finally, Dr. Boyer gave an overview of a number of oral medications that are visual-cycle modulators, decreasing the metabolic demand of rods and cones to try to prevent accumulation of toxic byproducts of visual transduction.

FRIDAY'S SESSIONS: DIABETIC RETINOPATHY

On Friday, the focus shifted away from AMD toward diabetic retinopathy. Jay Duker, MD, gave an overview of the pros and cons of different imaging modalities in diabetic retinopathy, concluding that while clinical diagnosis at the slit lamp is still the gold standard, optical coherence tomography will be important for redefining clinically-significant macular edema.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative network dedicated to facilitating multicenter clinical research of diabetic retinopathy, DME and associated conditions. Diana Do, MD, gave an overview of the results of the most recently published DRCR.net trials, looking at anti-VEGF therapy with ranibizumab vs laser and triamcinolone for the treatment of DME. The trial found that patients receiving ranibizumab with either prompt or deferred laser had better VA outcomes than laser alone. Pseudophakic patients receiving triamcinolone with laser did as well as patients receiving ranibizumab, but phakic patients did worse secondary to cataract formation. The discussion afterwards focused on why everyone does not use these results in their clinical practices, with the difficulty in understanding the retreatment protocol being one of the biggest obstacles to adoption. Dr. Do then presented the results of the DAVINCI trial, looking at VEGF Trap-Eye for DME and showing that VEGF Trap had superior VA outcomes to laser.

Dr. Chow presented his experience with the role of vitrectomy in the management of DME. If there is clinical or OCT evidence of traction on the retina resulting in DME, then vitrectomy is very effective, with removal of the posterior hyaloid being key to a successful procedure, while ILM peeling is debatable. However, there are no studies showing the efficacy of vitrectomy in DME if there is a PVD present. There are still many other questions regarding the role of vitrectomy in DME, but most of the studies that have been done are small, retrospective chart reviews, so there is a need for prospective analysis.

Intravitreal steroids have been shown to be effective in the treatment of DME; Dr. Kaiser presented the results of two different fluocinolone implants for DME. Retisert (Bausch + Lomb) is a surgically-implanted fluocinolone implant that elutes drug for three years and is approved to treat chronic noninfectious uveitis. Unfortunately, there is a very high incidence of cataract and IOP elevation that makes it a poor choice for the treatment of DME.

Iluvien (Alimera) is an injectable sustained-release fluocinolone insert that has completed phase 3 trials and that elutes a lower dose than Retisert, does not require a vitrectomy for insertion and lasts for two years. The phase 3 trial in patients with persistent DME showed good VA improvements with minimal IOP elevation but required cataract surgery in 80% of patients. Iluvien is currently awaiting FDA approval. Attendees debated the utility of these sustained-release implants in DME and where they would fit into their treatment schema.

Dr. Boyer gave an overview of multiple novel therapies currently in early-phase testing for DME. The final session on Friday was a series of interesting uveitis cases presented by Daniel Martin, MD, and Sunil Srivastava, MD. These presentations were followed by a discussion of the role of early, aggressive systemic therapy for noninfectious uveitis.

SATURDAY'S SESSIONS

Saturday morning's session was split into retinal and general ophthalmology tracks. The retinal track discussed issues with retinal surgery, while the other track focused more on retinal issues relevant to general ophthalmologists. The first talk in the retinal track was by Dr. Moshfeghi, who discussed issues that are important in pediatric retinal surgery. Dr. Chow discussed issues in the management of primary retinal detachments. Dr. Duker discussed tips and tricks during macular hole surgery. Finally, Dr. Dugel gave pointers that can be used during microincision surgery.

Microplasmin is a molecule with structure similar to plasmin and proteolytic activity against major components of the vitreous and vitreoretinal interface. Dr. Dugel discussed the MIVI-Trust trials, which found high rates of full-thickness macular hole closure following intravitreal injection of microplasmin. Discussion of the role of vitreomacular adhesion in other retinal diseases followed, as well as the role microplasmin may play in treatment.

After Dr. Dugel's talk, the two groups recombined for a talk by Marc Levy, MD, and Dr. Martin, discussing the implantable miniature telescope (IMT) recently approved for AMD. Surgically implanted in one eye, the IMT replaces the natural lens and provides an image that has been magnified more than two times, resulting in relative scotoma size reduction and improved visual acuity. The discussion focused on the need to manage the expectations of patients who will be getting the device.

• Retinal Vein Occlusion. The afternoon session focused on the treatment of RVO. The first talk, by Quan D. Nguyen, MD, discussed the results of the SCORE trial, which evaluated the clinical benefits of intravitreal triamcinolone for treating macular edema associated with RVO. SCORE was split into two separate trials: one compared observation vs triamcinolone intravitreal injection for central RVO while the other compared macular grid laser vs triamcinolone intravitreal injection for branch RVO.

In the CRVO trial, patients treated with triamcinolone were five times more likely to experience a gain of three lines of vision or more at one year compared to observation. The BRVO trial showed that grid laser had similar visual acuity outcomes at one year compared to triamcinolone. Given the poor safety profile of triamcinolone, grid laser remains a viable treatment choice for patients with BRVO. For both trials, patients who received the 4 mg dose of triamcinolone had much higher rates of IOP elevation and cataract formation compared to the 1 mg dose.

Dr. Srivastava discussed a sustained-release dexamethasone implant (Ozurdex, Allergan) for RVO and uveitis. Pharmacokinetic studies of the sustained-release dexamethasone injectable implant have shown that peak drug release is at 60 days and trails off afterwards. This results in the drug having efficacy for approximately three months prior to requiring another injection. The application of this implant may be limited for RVO and uveitis, given that there are other options that are longer lasting.

Dr. Nguyen then took the stage again to discuss the results of the BRAVO and CRUISE studies evaluating ranibizumab for BRVO and CRVO, respectively. BRAVO and CRUISE compared two different doses of ranibizumab given monthly vs sham injections. Rescue laser could be performed at three months if there was no benefit from the treatment. Both of the trials had similar results at six months, showing that both ranibizumab doses resulted in significant gains in vision compared to sham injection. This contrasted with the SCORE trial results for BRVO, in which triamcinolone was found to have no benefit over laser treatment. These results clearly suggest that early treatment of CRVO and BRVO with anti-VEGF may be the best treatment modality at this time.

Dr. Boyer gave the final presentation of the symposium, discussing the results of the COPERNICUS trial evaluating VEGF Trap-Eye for CRVO. VEGF Trap was found to result in significant improvement in vision in CRVO patients compared to sham at six months. The results mirrored the results of ranibizumab for CRVO in the CRUISE trial. VEGF Trap-Eye is still awaiting approval by the FDA.

MORE TO COME

Beginning with the June 2011 issue, Retinal Physician will begin a series that provides in-depth coverage of several lectures from the 2011 symposium per installment; we'll also share early details about the 2012 meeting. RP