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The Macula Expert is in Town

The Macula Symposium Singapore was held on June 10-11, 2017, courtesy of Singapore National Eye Centre (SNEC). International retinal specialists turned up in the island nation to beat down retinal vascular and macular diseases.

Transforming Science to Reality with Aflibercept

In the evolution of anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of neovascular age-related macular degeneration (AMD), aflibercept was the last drug on the market. 

However, as heavily reported in literature, it appears to have theoretical advantages over other anti-VEGFs: it had a much greater binding affinity to VEGF-A; it binds to placental growth factor (PGF) 1 and 2, and all isoforms of VEGF-A and VEGF-B; and the vitreous half-life for aflibercept (4.8 days) was estimated longer than that for ranibizumab (3.2 days). Ophthalmologists have been using aflibercept for a while now and in the process have further understood its novel mode of action. 

At the recently held Macula Symposium Singapore, aflibercept took center stage once more. 

“We have seen how aflibercept performed superiorly in multiple studies compared to other anti-VEGF agents,” said Quan Dong Nguyen, M.D., M.Sc., professor of ophthalmology at the Byers Eye Institute, Stanford University School of Medicine, California, USA.

Every retinal specialist who has reported on the benefits of aflibercept has emphasized that the true value of this “VEGF-trap” is in its unique molecular design.

Specifically designed for strong, broad, and durable activity, aflibercept is a novel recombinant fusion protein for intravitreal injection that binds all isoforms of VEGF-A, VEGF-B, and PGF. “It binds more tightly to VEGF than the native VEGF receptors,” emphasized Dr. Nguyen. 

While all commonly used anti-VEGF agents inhibit all VEGF-A isoforms, noted Dr. Nguyen, aflibercept blocks VEGF-induced activation of VEGFR-1/2 with up to 92 times greater potency than ranibizumab and bevacizumab.

In mathematical models, reported Dr. Nguyen, the intravitreal activity of aflibercept is extended almost 3-fold compared with ranibizumab, suggesting that biological activity of aflibercept 2 mg at 83 days is comparable to that of 0.5 mg at 30 days. 

Also, aflibercept has a strict 1:1 binding ratio, it binds or traps both sides of the VEGF dimer. Hence, it does not form multimeric conglomerates, which may aggregate and induce an immune response.

“It is these unique properties of aflibercept that explain its bioactivity and efficacy against various retinal vascular diseases. It is not just a ‘VEGF-trap’ but also binds to PGF which is another promoter of angiogenesis,” Dr. Nguyen added.  

Together, these chemical properties support clinical finding of aflibercept’s efficacy, emphasized Dr. Nguyen.

Since its approval by the U.S. Food and Drug Administration (FDA) in November 2011 for the treatment of nAMD, aflibercept is also currently indicated for diabetic macular edema (DME), macular edema secondary to all types of retinal vein occlusion (branch or central RVO) regardless of perfusion status, and myopic choroidal neovascularization (CNV). 

Presenting about a proactive approach with aflibercept, Dr. Peter Kaiser, M.D., from the department of ophthalmology of the Cleveland Clinic in Ohio, USA, highlighted the need for real life data to compare with results of randomized clinical trials (RCTs). 

There is a need for real-life evidence to complement the data provided by RCTs, as most often there is a disparity between the outcomes observed from these two settings. In RCTs, patients are homogenous and are pre-selected. On the other hand, clinical patients are very diverse. 

Dr. Kaiser presented RCTs involving ranibizumab (and aflibercept as well) and noted that “ranibizumab did not demonstrate RCT-like effectiveness in a large population of nAMD patients in over three years.”  The vision gains seen in RCTs of ranibizumab have not been reflected in clinical practice, noted Dr. Kaiser.  

“In some cases, 83% of the patients even after 5 years of treatment continue to have retinal fluid,” he observed.

Aflibercept has a longer durability of action, as shown in RCTs such as the VIEW studies. Looking at the real life outcomes with aflibercept, these compare favorably to the results from pivotal aflibercept clinical trials. 

“Aflibercept real-life outcomes in nAMD compare favorably to those seen in RCTs,” reported Dr. Kaiser.

Evidence accumulated in aflibercept came from across the globe, representing diverse patient populations.  

“In these studies, we don’t see the drop in gain of vision through time as seen in ranibizumab outcomes,” said Dr. Kaiser. 

The treat-and-extend regimen, according to Dr. Kaiser, is the better regimen among all anti-VEGFs, not just aflibercept.  “You get the vision gain and maintain that vision gain through time in the treat-and-extend regimen,” he explained. “In addition, the treat-and-extend regimen enables a lower injection burden (and reduced number of doctor visits) to patients over time.” 

Good outcomes can be achieved and maintained with the licensed aflibercept posology in year 1, with treat-and-extend enabling a lower injection burden in year 2, noted Dr. Kaiser.

“Real-life evidence is important to look at and compare to RCTs. Long term real-life studies seem to demonstrate that the ‘as needed’ treatment regimen in ranibizumab is not as good as the treat-and-extend regimen in aflibercept,” he said.

“It appears that aflibercept is working well in real-life studies as in RCTs. Aflibercept delivers effectiveness in real-life settings due to its unique mechanism of action that delivers both efficacy and durability,” concluded Dr. Kaiser.

Furthermore, results of key trials of aflibercept in polypoidal choroidal vasculopathy (PCV), a sub-type of nAMD have been discussed as well at the Macula Symposium in Singapore. 

Being more common in Asia, it is important to talk about polypoidal choroidal vasculopathy (PCV), noted Prof. Wong Tien Yin, MBBS, MMed(Ophth), MPH, FRCS(Ed), FRANZCO, FAFPHM, PhD(Johns Hopkins), Medical Director of the Singapore National Eye Centre (SNEC) and senior consultant ophthalmologist sub-specializing in medical retina.

“It presents somewhat differently from the typical AMD and choroidal neovascularization (CNV). However, a lot of evidence suggests that PCV is a variant of type 1 CNV. The question therefore is, how do we now treat PCV?,” reported Prof. Wong. 

In the ophthalmic community, there are concerns surrounding the treatment of CNV with PDT (photodynamic therapy) in terms of safety, efficacy and cost. In his presentation, Prof. Wong also elaborated on the practical considerations of aflibercept monotherapy compared to alternative treatment options for PCV and noted that issues remain in the long-term outcomes of PDT in PCV. 

Then Prof. Wong presented outcomes of the PLANET study, a multi-centered study which primarily investigated the efficacy and safety of aflibercept monotherapy compared to aflibercept with rescue PDT in the treatment of PCV, and determined whether aflibercept monotherapy is non-inferior with rescue PDT (as indicated), based on best corrected visual acuity (BCVA) in PCV patients. The study’s secondary objectives were to estimate the proportion of PCV patients who require rescue PDT therapy and to determine to what extent rescue PDT therapy is beneficial in PCV patients who have suboptimal responses to aflibercept monotherapy. 

“At 52 weeks, aflibercept monotherapy leads to gain of more than 10 letters from baseline, high rates of polyp inactivation (over 80% of patients showed no evidence of active polyps) and over 85% of patients needed no rescue PDT treatment,” reported Prof. Wong. 

What about in the <15% of patients requiring PDT rescue? “The VA gains were similar in monotherapy versus active PDT rescue,” he said. Hence, there is no significant difference in BCVA gains between the monotherapy and active PDT, regardless of need for rescue requirement, highlighted Prof. Wong. 

Aflibercept monotherapy protocol demonstrated similar outcomes to aflibercept combined with rescue PDT –  suggesting that aflibercept monotherapy can be established as a first line treatment option for patients with PCV. 

“Aflibercept monotherapy leads to favorable vision gains and high rates of polyp inactivation. Results of the PLANET study are consistent with aflibercept monotherapy studies, including real-life studies,” said Prof. Wong. 

“Whether treat-and-extend regimen is suitable in the treatment of PCV, we have to wait for the second year PLANET study data,” concluded Prof. Wong. 

The second year of PLANET study will assess the efficacy of aflibercept treat-and-extend protocol in PCV, potentially leading to extended treatment intervals and a reduced injection number. 

Of Lasers and Anti-VEGFs

Prof. Dr. med. Frank G. Holz of the Department of Ophthalmology, University of Bonn, Germany, while discussing new perspectives in imaging and functional assessment of dry AMD, delivered the most interesting statement: “The holy grail of AMD therapy is prevent late-stage manifestation.”

Whether through the use of lasers or anti-VEGFs, the intention is to retard the progression of AMD. 

Prof. Robyn Guymer, MBBS, PhD, FRANZCO, deputy director of the Centre for Eye Research Australia and a professor of ophthalmology at University of Melbourne, Australia, presented results of a pilot study on the use of nanosecond laser to retard AMD progression. 

Results from the said study concluded that resolution of drusen continued over a 12-month period, and greatest functional improvement occurred in the treated eyes between 3 and 6 months. 

According to Prof. Guymer, a good question to ask would be: “Is the improvement in sensitivity really an indication that we are reversing the defect that leads to advanced AMD?” 

“The explanation for the bilateral effect is not yet known but being explored,” she noted, referring to the LEAD (Laser intervention in Early Age-related Macular Degeneration) study.

The LEAD study is an investigation of the safety and efficacy of sub-threshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). The study has a time frame of 36 months and is still on-going. 

“Based on initial results, the nanosecond 2RT laser warrants ongoing evaluation as an early intervention,” said Prof. Guymer. 

Speaking of laser in a separate session, Prof. Wong Tien Yin of SNEC posed a very important question: “In the era of anti-VEGF therapy, is there still a role for laser in the treatment of diabetic retinopathy (DR) and diabetic macular edema (DME)?”

We have seen the changing management in DME, from laser in the 80s, intravitreal steroids in early 2000s to intravitreal anti-VEGF agents in recent years. In proliferative diabetic retinopathy (PDR), on the other hand, are we going to see the change in management from panretinal photocoagulation (PRP) to anti-VEGF therapy? 

“However, for 50 years now, laser PRP remains the first line of treatment in PDR, with excellent structural and functional long -term outcomes and significant combined global clinical experience,” said Prof. Wong.

As reported in by Olson, et al. in JAMA (2015), highlighted Prof. Wong: “Clinicians with decades of experience observing and managing the long term complications of PDR understand that most patients with adequate PRP have stable retinopathy for many years.”

As far as PDR treatment is concerned, anti-VEGF is not superior to PRP; anti-VEGF is not cost-effective compared to PRP. Also, PRP has fewer visits and is less resource intensive,” explained Prof. Wong.

“Most patients with diabetes have at least one comorbid disease, and 40% have 3 or more. Thus, going for a monthly doctor visit with “eye injection” for PDR is not a priority,” he added. 

Why focal/grid laser in PDR? It has robust, long-term level 1 evidence in preserving vision, is overall safe, and is less resource intensive. Besides, noted Prof. Wong, anti-VEGF therapy requires compliant knowledgeable patients.  “There are significant gaps in knowledge and awareness among patients with DR and PDR,” he said.  

DME is a different story altogether, highlighted Prof. Wong. For DME with central involvement and vision loss, anti-VEGF therapy is now the gold standard. For DME without central involvement and good vision, there is a role for focal/grid laser. For DME with central involvement but good vision, clinicians can observe anti-VEGF versus focal/grid laser.

“In eyes with PDR, laser PRP remains the standard of care, with long-term efficacy and safety results, and is a widely available, cost-effective treatment,” Prof. Wong concluded. 

On Imaging Modalities

At the recently held Macula Symposium in Singapore, updates in imaging modalities abound in all sessions. Generally, in the management and treatment of ocular diseases, imaging plays a critical role –  from diagnosis to monitoring of efficacy of treatment. 

In recent years, there has been an exponential development in ophthalmic imaging. As much as anterior segment ophthalmologists are benefiting from the technology, retinal specialists have apparently more reason to be excited about it. The back of the eye has never been this much visible as it is today with innovations in wide-field flourescein imaging and in OCT technology, to name a few.

In inflammatory eye diseases, these imaging updates have become more useful than ever, noted Dr. Vishali Gupta, M.D., professor of ophthalmology at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

“Wide angle flourescein angiography is useful in examining the periphery in uveitis patients. Fundus autoflourescence is a useful non-invasive imaging modality for monitoring choroiditis,” reported Dr. Gupta. 

The advancements in Optical coherence tomography (OCT), spectral domain (SD) and swept source (SS), emphasized Dr. Gupta, are very useful for studying the vitreo-retina interface, the intra-retinal pathologies, retinal pigment epithelium (RPE) and choroid.

 “Optical coherence tomography angiography (OCTA) is a very useful non-invasive imaging modality with a newer view of the retina,” she added.

Editor’s Note: The Macula Symposium Singapore was held on 10-11 June 2017 courtesy of Singapore National Eye Centre (SNEC). Reporting for this story also took place at the said event.


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