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posterior segment • innovation • enlightenment
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PIE M A G A ZINE ’ S D A ILY CONGR E S S NE W S ON T HE P O S T E RIOR S E GME N T
HIGHLIGHTS injections, 04 it’sIn anti-VEGF what in the syringe that’s causing an issue... vitreoretinal surgery 07 New techs benefit both surgeon and patient. present 08 Experts management options for proliferative vitreoretinopathy (PVR).
Unlocking the ‘Deeper Secrets’ of Dry AMD by Joanna Lee
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What is a metabolite and what are the implications for AMD patients? Also, genetic implications seem to be fuel for research these days in an attempt to unlock deeper understanding into AMD.
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nowing the features of a disease is important as seen in two studies on pentosan polysulfate sodium maculopathy. The study, Pentosan Polysulfate Maculopathy versus Age Related Macular Degeneration: Comparative Assessment with Multimodal Imaging, looked at the distinctive imaging features that could be different from those found in AMD. They found that pentosan polysulfate sodium (PPS) maculopathy has a distinctive phenotype that can be differentiated from AMD. They also found AMD patients exposed to PPS had a significantly greater probability of having pigment clumps at the level of the RPE. The study’s presenter Dr. Joseph Christensen said: “Another key finding was on the fundus autofluorescence (FAF) imaging where you can see the dense array of the hyper and hypo autofluorescence spots – they tend to show up in pentosan maculopathy versus AMD”. Also of significance was a high number of hyperreflexive foci found in the pentosan group. The next study Pentosan Polysulfate Maculopathy: Disease Course after Drug Cessation by Dr. Rachel
Shah aimed to assess the progression rate of PPS where they found that PPS maculopathy continues to evolve in almost 75% of patients even after drug cessation. Cont. on Page 3 >>
HOTSHOT
ASRS has been great, but we all still miss physical conferences. In the meantime, consider yourself part of a new underground conference group — the Anti Social Social Club — as it’s a lot easier to keep your socializing expectations with social distancing in check that way. Pictured here: PIE magazine CEO Matt Young at Viking Barbershop (Da Nang, Vietnam) after a haircut during a break from the ASRS virtual meeting.
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27 July 2020 | Issue #4
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PIE magazine’s Daily Congress News on the Posterior Segment
>> Cont. from Page 1
Dr. Shah deemed the fundus autofluorescence and near-infrared reflective imaging as most helpful in documenting the growth in general and also measuring the growth in RPE atrophy. The next study was on Phase 1 Safety Study of intravitreal Anti-high Temperature Requirement A1 (aHtrA1), A Novel Serine Protease Inhibitor, in Patients with Geographic Atrophy (GA)”. The study found that single ascending doses (SADs) of anti-HtrA1 (ranging from 1 to 20 mg) as well as multiple doses of 20 mg administered every four weeks for 3 doses were very well-tolerated in patients with GA secondary to AMD. Enzyme activitybased pharmacodynamic (PD) assay also indicated a potential for an 8-week target inhibitor at higher doses. Dr. Zachery Bridges, who presented the study, said this approach is unique in that they’re neutralizing a serum protease which they see as genetically implicated in progressing to advanced AMD. Dr. Justis Ehlers and his team looked at the Impact of Baseline OCT Characteristics on Response to Risuteganib for the Treatment of Intermediate Age-related Macular Degeneration. The proportion of patients with greater than 8-letter gain in BCVA from baseline was about 48% in the group receiving risuteganib, compared with the 7.1% in the sham group. Dr. Ehlers also had two independent groups to look at OCT features which could possibly predict BCVA response to risuteganib. It was discovered that a higher central outer retinal thickness and a low-ellipzoid zone defect area are predictors of greater response to treatment. In the second Dry AMD Symposium, participants were introduced to the role of metabolomics in AMD. Patients with AMD have a distinct plasma metabolomics profile compared to controls while metabolomics may provide easily accessible AMD biomarkers that can be combined with imaging and genomic profiles to identify AMD subtypes. Dr. Deeba Husain explained: “Metabolomics is a new concept (to ophthalmology and AMD). It is the study of very small molecules in all our body and it is the downstream of all the genetic
processes, affected by diet, lifestyle and medical conditions, environment and medications. “Metabolites have been shown to be closely related to phenotypes of many other systemic multifactorial diseases,” shared Dr. Husain. “This is why we decided to investigate the role of metabolomics in AMD as we hypothesize we could address some of the unmet needs of this blinding disease,” she said. Her prospective multi-center double blind study included 491 subjects with AMD and two cohorts of control groups. Dr. Husain’s study also found the most significant metabolites relate to lipids and amino acids which included nitrogen, taurine and purine.
“Metabolites have been shown to be closely related to phenotypes of many other systemic multifactorial diseases.” “This work is exciting because it can become the basis of bio-fluid biomarkers for AMD,” Dr. Husain said. She added that this development may make it potentially available a blood test
for AMD which would tremendously help the elderly population at home. “Secondly, we have seen changes in metabolites in AMD and these metabolite changes can potentially be the target for new treatments for dry forms of AMD, for which we currently do not have any,” she added. In another presentation, Dr. David Sarraf’s investigations into Nonneovascular Age Relate Macular Degeneration and Fluid concluded that non-neovascular AMD with subretinal fluid (SRF) is an important clinical entity to recognize to avoid unnecessary antiVEGF therapy. “Fluid can complicate drusen and RPE may be related to pump failure, referred to as a transudate rather than an exudate,” he said. On how to differentiate between transudate versus exudate, Dr. Sarraf said: “The OCT-A can be very helpful in diagnosing the presence of macular neovascularization.” A randomized multi-national study by Dr. Baruch Kupperman looked into a novel C5 inhibitor called avacincaptad pegol, better known by its brand name Zimura, showed how complement C5 is a viable target for inhibition to potentially slow RPE cell death in patients with GA. The primary efficacy endpoint was achieved for both 4 mg and 2 mg doses which effected a 27% reduction in GA.
Progressions in dry AMD research may get some sufferers looking on to the bright side.
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27 July 2020 | Issue #4
Injections, Injections, Injections,
Needing the Needle or Not by Sam McCommon
T
he last day of the virtual American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020) featured a slew of wet-AMD symposia. Among these presentations were data on much anticipated treatments, including the port delivery system for ranibizumab that’s been undergoing trials. This system would potentially bypass the need for frequent injections. And, on the topic of injections, enlightening information was presented on the link between injections and inflammation. More on each below…
Port delivery system of ranibizumab shows promise One major study introduced in today’s wet age related macular degeneration (AMD) session is a port delivery system (PDS) that provides a constant flow of ranibizumab. Dr. Peter Campochiaro shared data on the system that appears thoroughly optimistic. The delivery system is an implant roughly the size of a grain of rice. According to data presented by Dr. Campochiaro from the ARCHWAY study, the PDS allows for equivalent vision management and controlled retinal thickness as repeated brolucizumab injections. The reduction in treatments was significant: On average, patients with the PDS system needed five times fewer treatments than those in the standard group, and 98% of PDS patients didn’t receive supplemental treatment before their first refill at 24 weeks. Dr. Campochiaro’s main takeaway? A 24-week treatment with a brolucizumab PDS was equivalent to monthly treatments, and had a favorable riskbenefit profile. He did mention risks
treatment should be customized to the patient. When asked about the real-world viability of a PDS, Dr. Eichenbaum said: “You’ll probably get six to nine months or perhaps longer in some patients.”
Even a standard medical tool can be subject to competition and upgrades.
worth paying attention to: conjunctival erosion and retraction. Specifically, he noted that both conditions raised the risk of endophthalmitis, so any conjunctival problems should be closely monitored. Dr. Dilsher Dhoot further drew on the ARCHWAY study and confirmed the efficacy of the PDS, pointing out that serum levels of ranibizumab were within the range of intravitreal monthly control patients, which was consistent after the first and second refills. “Overall, these data add to our confidence that these patients are receiving therapeutic treatment at six months and beyond.” The drug would be especially useful in allowing patients who require monthly injections to have a reduced burden of treatment, he said. Dr. David Eichenbaum presented the LADDER phase 2 trial, also covering the PDS of ranibizumab. In this study, patients went longer before a refill —a median of 15.9 months. Patients who met the criteria for a refill exhibited the same amount of time necessary between refills: 8.8 months each time. He added that wet AMD is a heterogeneous condition, and each
How to follow up? “With anything new, follow patients closely at first and as the community gets more comfortable and the data rolls out we’ll let out the line,” he explained.
The syringe as a cause of inflammation? One potential reason doctors may wish to minimize injections was found in information presented by Dr. Gustavo Barreto de Melo. A randomized, doubleblind, controlled study showed that agitation (i.e. flicking) of a siliconized syringe seemed to cause inflammation. Specifically, agitating the syringe released silicone oil, which Dr. De Melo said could be the main cause of the inflammation. The group subjected to an agitated siliconized syringe experienced a statistically significant amount of inflammation compared to the control group. The takeaways? First, he suggested that syringes should not be agitated. Second, the use of a silicone oil-free syringe might be protective against inflammation. Third, syringes that release little or no silicone oil should be preferred.
PIE magazine’s Daily Congress News on the Posterior Segment
Treatment Advances in nAMD Coming Soon to an O.R. Near You by Brooke Herron
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et (or neovascular) age related macular degeneration (nAMD) is a chronic and sight-threatening eye disorder — and to maintain (or restore) vision, early detection and treatment are key. However, these treatments, usually in the form of antiVEGF injections, are not always the “golden ticket.” In the case of anti-VEGF, the therapy can be costly and the treatment burden can be high — plus, some patients don’t respond. Therefore, constant research is being done to create and assess new treatment options and regimens. Some of these advances were covered during the Wet Age-Related Macular Degeneration Symposiums (3-4) on the last day of the American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020).
New agents show promise Kicking off the session was an update on the phase 1b study of the novel intravitreal anti-VEGF antibody biopolymer conjugate (ABC) KSI-301 by Mark R. Barakat, MD. Antibody biopolymer conjugates (ABCs) are biologics engineered for increased durability and efficacy with improved specificity, affinity and tissue access; in particular, KSI-301 is an anti-VEGF ABC designed to block all VEGF-A isoforms. With study results demonstrating that KSI-301 shows promising safety, efficacy and durability, queries turned to treatment duration and regimens. Moderator Christina Weng, MD, pointed out that, “Impressively, nearly half (49%) of patients were able to reach 6 months before having their first retreatment.” She continued that the retreatment criteria differed as well — rather than to treat to dry, this was based on visual acuity and investigator discretion. So, could this affect treatment regimens?
According to Dr. Barakat, if the retreatment criteria were not met and the investigator thought there was significant disease activity, treatment was allowed. “In terms of fluid or no fluid, I know there’s some debate about that right now . . . in the long run, if you keep the vision stable that’s what you’re going for,” he concluded.
Timing is everything Next, Peter Kertes, MD, answered questions regarding the Canadian Treat-and-Extend (T&E) Trial with Ranibizumab in nAMD Patients: CANTREAT 36-Month Extension Results, which compared T&E and once-monthly treatment regimens. Dr. Kertes found that the mean change from baseline in BCVA at 36 months was 6.3 (11.61) letters for the T&E group and 3.9 (13.91) for the once-monthly group. “The purpose of presenting this three-year data is to show that Treatand-Extend is a durable treatment strategy where the visual gains can be maintained long-term,” he shared. “This study was conceived during a time when most of us were practicing Treat-andExtend, but there really wasn’t any good level one evidence to support it. So I find it reassuring that it’s non-inferior to once monthly for as long as three years.” T&E is being embraced by patients and physicians alike as it reduces the treatment burden while maintaining vision. “We worry about treatment burden in our patients, and when we looked at patients who were lost to follow-up, what we found is that they averaged about 15 months of therapy . . . so, these weren’t patients who were
New treatments for nAMD may be closer than they appear.
treated with one or two injections and decided they didn’t like it,” shared Rahul Khurana, MD. In this vein, Rahul Komati, MD, then discussed Treatment Burden and Vision Analysis of Anti-VEGF Therapies for the Treatment of nAMD. “What we found, despite the variability of different [anti-VEGF] agents, there was a positive and clinically meaningful correlation between the number of injections at 12 months and the change in visual acuity,” explained Dr. Komati. “The opportunity for longer acting agents and longer dosing regimens still holds incredible value.”
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27 July 2020 | Issue #4
The Cutting Edge of Wet AMD Management by Sam McCommon
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mong the many wonderful presentations during the wet AMD symposia were some truly forward-thinking presentations featuring new technologies. We’re always happy to see new technology added to ophthalmologists’ arsenals, especially when it leads to convenience and safety. These technologies all featured a bit of a ‘wow’ factor and will likely be making waves in the ophthalmic future.
Catching nAMD before it starts In the modern climate of stay-athomeness, anything that can be done at home instead of in a clinic is a big plus. One such system was ForeseeHome AMD Monitoring Program (Notal Vision, Virginia, USA), presented by Dr. Allen Ho. He shared data on the system’s effectiveness in the real world. It’s already FDA cleared for early detection of wet AMD, so it’s interesting to compare real-world data to clinical trials. Good news: ForeseeHome performed as well in the real world as it did in the study. Dr. Ho noted that preserving 3-4 lines of vision at the onset of nAMD leads to better visual acuity prognosis with anti-VEGF therapy. So, how does it work? First, a physician writes a prescription and then sends it through the electronic health record. Then the prescription goes to the remote
or diagnostic clinics, which send the hardware to the patient, train them, and monitor them for compliance. The ForeseeHome system is hooked up to a cell modem. The data (generated by patients when they use it) goes to a central monitoring site, called the Notal Vision Diagnostic Center. If there’s an alert of nAMD development, both physician and patient can be notified.
A bit of gene therapy Another neat bit of technological endeavor is RGX-314. It’s being developed as a one-time treatment for both nAMD and diabetic retinopathy. It delivers a gene that neutralizes VEGF activity — and it’s showing some promising results among five cohorts of a long-term study. Dr. Arshad Khanani presented data on the ongoing phase I/II trials for RGX-314 in treating nAMD. So far it has been well-tolerated at all dose levels. In fact, its durable treatment effects have been demonstrated over two years in cohort 3 of the study. The effects include improved visual acuity and stable retinal thickness, a significantly reduced treatment burden, and stable intraocular RGX-314 protein expression. Cohorts 4 and 5 showed stable to improved vision and OCT after 6 months, and in cohort 5, 73% of patients remain anti-VEGF injection free at 9 months. Across all cohorts, intraocular RGX-314
protein levels at 6 months demonstrate dose-dependent expression. Being able to reduce treatments to a one-time affair would be very valuable — the next stages of the trial will be watched with anticipation.
Deep learning algorithms and home images In another technological development, Dr. Judy Kim presented a novel deep learning algorithm for automatic retinal fluid quantification in home OCT images. An algorithm can accurately sift through a large volume of OCT images with high accuracy. It can use these images to track disease activity biomarkers, which can lead to personalized AMD management. The Notal OCT Analyzer (NOA) from Notal Vision (Virginia, USA) has been shown to analyze intra- and sub-retinal fluid volumes with high pixel-to-pixel correlation, sensitivity, and specificity when compared to a human grader. The algorithm is so specific in its analysis that it can detect even a picoliter of fluid in a real-world setting following a patient over a period of time. In layman’s terms, that’s an extremely tiny amount. The use of home monitoring is also ideal for our current medical climate, in which people want to minimize clinic visits as much as possible.
PIE magazine’s Daily Congress News on the Posterior Segment
New Technology Benefits Both Patient and Surgeon by Brooke Herron
As to the benefit of cooling anesthesia, Dr. Chao said: “All of the four types of anesthetics would effectively and safely perform the injection, but we think that it’s the patient and physician experience that may really benefit. “We don’t think that cooling anesthesia is providing superior pain control at the time of injection, but because of the rapid onset of the anesthesia and the
Up next was Christopher Henry, MD, to discuss suprachoroidal injections. “These injections are not difficult to perform, 98% of baseline injections were able to be completed successfully; 71% with the short needle; 29% with the longer 1100 µm needle. So, don’t be nervous about these injections, they’re easy to learn and I think that in the future, this is going to be a promising technology,” shared Dr. Henry.
is in on i s t o h
Next, Dr. Chao discussed his results on Cooling Anesthesia for Intravitreal Injection with a Novel Device: Results from the Prospective COOL-2 Study.
a retina surge
Keep your cool
“For me, it helped reinforce that we can cross a lot more than maybe we intuitively think . . . we’re always so concerned with not bumping the crystalline lens and avoiding complications, but it was very helpful to get that confidence, especially in eyes where we want to do peripheral work, where we don’t need to take the crystalline lens, and we can do a lot more crossing over with better visualization of the vitreous,” concluded Dr. Sridhar.
A painte r is to his brush as
So, did prior experience with digital systems influence these results in subjective usability? The answer is yes. People that had used digital microscopes before were less likely to be bothered by even higher levels of latency, according to Dr. Kim.
Jayanth Sridhar, MD, then looked at Lens and Peripheral Retinal Relationships during Vitrectomy: Comparison of 23-, 25- and 27-gauge Vitrectomy and Curved Endolaser Probes. This paper was based on a 1991 study by Smiddy et al. which identified the relationship between vitrectomy instruments and the phakic lens in the eye — this study re-examines those relationships using smaller instruments. As it turns out, the gauge of the instrument did not matter. However, they found that curved instruments could come closer to the ora serrata (180 degrees from the entry site). Another interesting finding was that in eyes with an axial length of ≥25mm, the vitrector can cross the ora serrata.
Finally, a new device made its virtual debut at ASRS 2020: The PINNACLE 360™ 25-gauge Scleral Fixation Forceps from Bausch + Lomb (Bridgewater, New Jersey, USA). Developed in conjunction with Arizona retina specialist Daniel Adelberg, MD, these forceps aid in the placement of scleral-sutured posterior chamber intraocular lenses (IOLs) – a procedure that has played an important role in the treatment of aphakic eyes without capsule support.
s.
The first paper assessed was The Effect of Latency on Digital Retinal Surgery by David Tri Ta Kim, MD, and Daniel Chao, MD. The authors found no significant difference in performance associated with different digital latency levels (50, 66, 90 and 122 milliseconds) and concluded that differences in latency have no negative impact.
Different probes for different folks
Shiny and brand new
e nt
Latency: No bother
ability to perform the injection right after the anesthesia . . . these may have unique benefits,” he concluded.
um str
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he continued innovation of ophthalmic instrumentation and devices has revolutionized vitreoretinal surgery — today, surgeons are able to view the posterior segment more clearly than ever before and new tools can provide added efficiency and safety. Therefore, on the last day of the American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020), experts convened to discuss the latest advances during the Instrumentation and Devices Symposium.
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27 July 2020 | Issue #4
A Potential Management Tool for Proliferative Vitreoretinopathy by Sam McCommon
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anagement options for proliferative vitreoretinopathy (PVR) was a major topic during the retinal detachment symposium at the virtual American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020). One potential drug discussed was methotrexate. The drug blocks DNA synthesis and inhibits chromosomal replication. Dr. Scott Walter presented a study on the drug’s effectiveness. He indicated
it should be used for postoperative management of PVR after surgery to prevent recurrence. Dr. Walter said: “Methotrexate is an antimetabolite drug that’s been proven effective in stopping PVR cells in vitro. Intravitreal methotrexate is currently undergoing a phase 3 clinical trial which is aimed at demonstrating its efficacy in preventing retinal detachments from PVR.�
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His patients were treated with a less intense treat-and-extend protocol as opposed to more frequent doses. They received treatments at one- to two-week intervals until the edge of the retinectomy was stable, with around three injections during the first postoperative months. Following that, injections were administered at three to six week intervals, with around two injections during the second and third postoperative month. “The results showed a significant improvement in mean visual acuity, with a 78% increase in ambulatory vision,� said Dr. Walter. There was a single operation success rate of 88%, with a final reattachment rate of 96%. He noted that 40% of eyes developed corneal toxicity, which should be treated aggressively, though dosage may play a role. “The corneal toxicity may be dose-dependent,� he said. “I generally found that the toxicity generally did improve with more extended dosing intervals, so this treat-and-extend approach allowed us to modify our treatment of patients who were having more toxicity.�
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