A New Era in the Treatment of Hereditary Optic Neuropathies

by Olawale Salami

Should these treatments prove to be effective and safe, they will radically transform the treatment approach to patients at risk of visual loss. Gene therapies are emerging for several inherited retinal diseases as well. These recent scientific and clinical developments may represent the beginning of an era of approved gene therapies for a wider range of neurologic diseases.

Retinal degenerative diseases are a leading cause of irreversible blindness. The central pathology in many of these conditions is retinal death, induced by a mix of genetic and environmental factors. Inherited conditions are increasingly recognized as an important component of the neuro-ophthalmic differential diagnosis of sub-acute vision loss. For these blinding conditions, innovations in gene and cell therapy approaches offer therapeutic intervention at various disease stages.

A recent review by Dr. Tatiana Bakaeva et.al from Harvard Medical School, Boston sheds light on hereditary optic neuropathies. 1

A journey in discovery

For experts in the field, it’s been a long journey towards understanding the pathophysiological pathways that underlie degenerative retinal diseases how these insights translate into the development of novel treatments. The investigators reported that: “To date, many promising treatments have been showing disappointing results in human trials. However, newer insights into the genetic basis, natural history and phenotypic heterogeneity of these conditions have set the stage for targeted therapies that are moving into clinical trials.” Leber’s hereditary optic neuropathy (LHON) is an important example, in which visual loss can be severe and permanent. It is associated with three primary pathogenic mitochondrial DNA mutations, with varying degrees of penetrance, suggesting additional environmental factors. A variety of treatments have been tried in the past including systemic steroids, hydroxycobalamin and cyanide antagonists, vitamin C and riboflavin. The results were disappointing. However, a new class of drugs has shown promising results in clinical studies. These are known as CoQ10 analogues, or mitochondrial “cocktails,” They interact with the mitochondrial electron transport chain to facilitate mitochondrial electron flux and bypass complex within this class, Idebenone and EPI-743 have appeared to be the most promising judging by early results from clinical trials showing a trend toward preserved acuity and RNFL thickness. However, as reported by Dr. Bakaeva and colleagues, data from larger studies are needed to validate these results.

Bridging the genetic gap

Given the unspecific nature of existing therapies for LHON Experts in the field have evaluated gene therapy as a targeted therapy that could effectively and safely prevent visual loss in highrisk but pre-symptomatic patients. The past decade has brought an exciting set of advances in gene therapy for this condition. Using genetically engineered vectors, most commonly the adenovirus 2 experts have assembled replacement genes, like the human ND4 gene, that hopefully will be efficiently expressed by the vectors and carried into the mitochondria, to replace deficient genes in the eye tissue of patients, and restore vision. Impressive results in in-vivo animal studies have led to early phase human studies at various stages of completion.

In other inherited retinal conditions, research and development in new therapeutic strategies have progressed much further. Leber’s congenital amaurosis (LCA) is a spectrum of inherited retinal disorders, characterized by severe visual impairment presenting at birth or within the first few months of life, usually accompanied by roving eye movements or nystagmus, poor pupillary responses, and severely abnormal full field electroretinogram (ERG). 3 At present, there are 24 known gene mutations and the most common mutation occurs in the RPE65 gene, which accounts for approximately 16% of cases. Until recently, management of most forms of LCA has been symptomatic, but the previous decade has brought major scientific advances leading to a major breakthrough in the treatment of the specific form associated with mutations in the RPE65 gene. 4 Gene therapy for RPE65-associated retinopathy is commercially available, but prohibitively expensive, beyond the reach of many patients. 5

Choroideremia is a rare disease characterized by progressive degeneration of the choroid, retinal pigment epithelium (RPE), and photoreceptors, starting with night childhood blindness that ultimately progresses to severe blindness. It has an X-linked recessive inheritance pattern caused by a loss of function mutation in the CHM gene that encodes REP1 (Rab escort protein 1). In other hereditary and nonhereditary retinal diseases in which gene therapy is being explored include achromatopsia, retinitis pigmentosa, X-linked retinoschisis, Usher’s syndrome, Stargardt’s disease, and age-related

macular degeneration, clinical studies of novel gene therapy-based treatments offer the promise of long lasting restoration of vision.

What about stem cell therapy?

Stem cell therapies are being explored extensively as treatments for degenerative eye diseases, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. 6 Stem cell therapy may offer an opportunity for restoring vision for patients in whom the extent of structural damage is too severe for effective gene therapy. These conditions can include chronic LHON and other acquired optic neuropathies, as well as most inherited retinal degenerations including retinitis pigmentosa.

Unlike gene therapy that is intended to enhance the function of poorly functioning existent cells, the goal of stem cell therapies is to regenerate dysfunctional tissue and restore lost cells. There have been many promising animal and preclinical studies over the past 20 years that involve the use of embryonic induced pluripotent and bone marrow–derived stem cells for retinal and neurologic diseases. Ongoing research is focused on optimizing techniques that allow safe delivery of an adequate number of cells to the recipient eye with the appropriate development of tissue structure. Several clinical trials are focused on treatment of age-related macular degeneration and other inherited retinal degenerations.

In contrast to progress being made in rigorous, well-conducted studies, patients and clinicians should be aware of an alarming trend of commercially advertised stem cell treatments that are not regulated, with substantial risk of poor outcomes including endophthalmitis, cataract progression, fibrous proliferation and tractional retinal detachment, and retinal artery occlusion following subretinal, intravitreal, and/or periocular injections of bone marrow–derived stem cells. 7

Translation to clinical setting

LHON and other genetic causes of visual loss are important clinical entities that can cause profound visual loss. To date, therapeutic options have been quite limited. Insights into the genetic basis of these diseases and advances in the ability to deliver effective and safe gene therapy have opened the door for new therapeutics that may revolutionize the approach to treating these conditions.

While carefully conducted, controlled studies are keys to understanding the effects of these potential treatments and defining the optimal treatment populations, how do all these translate to real-world clinical setting? More importantly, the crucial first step is diagnosis. “In trying to arrive at the diagnosis, it would be helpful to examine parents and/or siblings, as many genetic conditions, though may have variable penetrance and expressivity, may have some detectable clinical manifestations,” shared Dr. Manoharan Shunmugan, vitreoretina

References:

Bakaeva T, Mallery R, Prasad S. Emerging Treatments for Leber’s Hereditary Optic Neuropathy and Other Genetic Causes of Visual Loss. Semin Neurol. 2019;39(6):732-738. Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 2013;5(189):189ra76. Fazzi E, Signorini SG, Scelsa B, et al. Leber’s congenital amaurosis: An update. Eur J Paediatr Neurol. 2003;7(1):13-22. Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2231-9. Apte RS. Gene Therapy for Retinal Degeneration. Cell. 2018;173(1):5. Mead B, Berry M, Logan A, et al. Stem Cell Treatment of Degenerative Eye Disease. Stem Cell Res. 2015;14(3):243-57. Herberts CA, Kwa MSG, Hermsen HPH. Risk Factors in the Development of Stem Cell Therapy. J Transl Med. 2011;9:29. specialist in Kuala Lumpur, Malaysia.

Having a special interest in hereditary degenerative neuropathies, Dr. Shunmugam highlighted critical points on this subject matter, including genetic counseling. “For patients with hereditary conditions it is imperative that the parents receive genetic counseling so that they are aware of the possibilities of these conditions affecting any other children. It would also be prudent to ensure siblings or extended families have a routine eye examination,” he explained. Furthermore, a thorough social and dietary history is necessary, according to Dr. Shunmugam. “Some modern dietary restrictions have been shown to have an impact on even normal individuals let alone those with underlying genetic conditions,” he added.

Contributing Doctor

Dr. Manoharan Shunmugam is a consultant ophthalmologist, adult and pediatric vitreoretinal surgeon who trained in the United Kingdom and returned to Malaysia in 2012. He has a keen interest in research with publications in a wide-range of highimpact journals and has been invited to many international conferences as a speaker. He is also a contributing author of two book chapters in vitreoretinal reference textbooks. He graduated in Scotland and subsequently undertook his Ophthalmic Specialist Training and VR Fellowship in London. En route, he further honed his skills with a Pediatric VR fellowship at L.V. Prasad Eye Institute, Hyderabad, India – making him one of the few pediatric VR surgeons serving the Asia-Pacific region. Today, he continues to serve at Hospital Kuala Lumpur, Pantai KL & Assunta Hospital. He is also the Hon. Secretary of the Malaysian Society of Ophthalmology (MSO), and is a member of the Asia-Pacific Vitreoretinal Society (APVRS) and the American Society of Retinal Specialists (ASRS).

manoshun@gmail.com

Beovu: What’s the latest with the ophthalmic community’s concerns?

by Sam McCommon

Reports and opinions keep pouring in about Novartis’ Beovu® (brolucizumab), meant to treat wet or neovascular age-related macular degeneration (nAMD). In February, the American Society of Retina Specialists (ASRS) noted a risk of intraocular inflammation and retinal vasculitis associated with the drug; more concerning was that 11 of the 14 cases of vasculitis were occlusive retinal vasculitis, which can lead to vision loss. The drug’s main appeal is that it reduces the rate of injection to once a quarter following the initiation of treatment.

Novartis backed these findings in April, noting a “confirmed safety signal of rare adverse events of retinal vasculitis and/ or retinal vascular occlusion that may result in severe vision loss.” Novartis’ safety review committee (SRC) noted a 3.3% rate of retinal vasculitis in study patients who had been treated with Beovu. Most of the patients (74%) experienced symptoms within six months of the treatment, though some (12%) experienced it as late as 12-18 months afterwards. According to an ASRS report, the earlier events were associated more frequently with moderate or severe vision loss.

Fast forward to May, and an editorial in the American Journal of Ophthalmology asked if this was a 737 MAX moment for brolucizumab, drawing a connection between the drug and Boeing’s flawed flyer. Authors Philip J. Rosenfeld and David J. Browning asserted that, as there are other drugs currently available to treat wet AMD, there is no reason to subject patients to the risks associated with Beovu. They argued that previous warnings hadn’t gone far enough: While announcements from the ASRS and Novartis did note the risks associated with the drug, they didn’t call for stopping its use. These authors took that stop and called for its halt. “In the face of the known risk, its use is unwarranted,” they wrote. “We praise the post-marketing surveillance of the vitreoretinal community in identifying these never-events, but now we need the ASRS, the Retina Society, the Macular Society, the AAO and the FDA to make official what many retina specialists have already implemented — a moratorium on its use until the results of further investigations are concluded and remedies are implemented.”

Other drugs currently on the market have not been associated with the same levels of intraocular inflammation (IOI). As the authors said, “The retinal community had not reported this type of vision-threatening occlusive retinal vasculitis after intravitreal injections of other commonly used anti-VEGF drugs, such as aflibercept (Eylea; Bayer, Leverkusen, Germany), bevacizumab (Avastin; Genentech, California, USA), and ranibizumab (Lucentis; Genentech, California, USA). Retinal specialists

started sharing this brolucizumab information with each other through social media, at meetings and through published reports.”

So the new kid on the block has raised a few eyebrows. Where are we now? To get a clearer view of the picture, we reached out to Dr. Kenneth Fong, president of the Malaysian Society of Ophthalmology.

Doctor’s orders

Dr. Fong acknowledged the concerns brought up by the ASRS and confirmed by the SRC. “These reports of retinal vasculitis in patients receiving brolucizumab are very concerning as such side effects have not been observed in millions of patients treated with the current choices of anti-VEGF agents: bevacizumab, ranibizumab or aflibercept,” he said.

“Patients receiving brolucizumab should be informed of this potentially serious side effect before treatment,” he added. Doctors who administer the drug should be aware of the current findings, and pass the information along to their patients.

Dr. Fong noted that he has only used Beovu for a small number of patients as part of a study that compares the drug to aflibercept for diabetic macular edema (DME).

Is it any use at all?

Despite the calls for the drug’s use to be halted by the authors of the AJO op-ed, there may still be some use for Beovu. However, it may not be the go-to, frontline drug for nAMD that Novartis had previously planned.

“In my practice, brolucizumab is a potential second line agent for patients that have not responded to the current line of anti-VEGF agents available, which all have excellent long-term visual acuity gain and safety profiles,” said Dr. Fong. “Despite the fact that it is FDA approved for wet AMD, it would be hard to recommend it as a first line agent until the safety issues have been clarified further.” Dr. Fong further pointed out that the risk of serious vision loss — a loss of more than 15 letters — was at 0.7% according to the current studies. So, while upwards of 99 out of 100 patients do not suffer severe vision loss, the risk is still there. Nobody wants to be that one in 100.

To Novartis’ credit, they’ve received praise from the ophthalmic community for their transparency and quick action regarding the drug. Once the risks are better understood, the drug could come roaring back and be that frontline player it was meant to be. The company defended the drug’s value as a treatment and reaffirmed their commitment to transparency.

As a company spokesman said, “Novartis believes that Beovu continues to represent an important treatment option for patients with wet AMD, with an overall favorable benefit-risk profile. We are committed to collaborating with the scientific community to better understand the causes, potential risk factors and management of these events.”

What’s next for Beovu?

The drug is being investigated, as the reason behind its link to IOI is still unknown. The drug is still on the market, and its use will have to be decided at each doctor’s discretion. As the ASRS’s ReST committee noted, “With all therapeutics, the risk of adverse events and their visual consequences need to be balanced with potential benefits. The ReST Committee believes that this riskbenefit assessment at the individual patient level is best determined by the judgment of the treating provider.”

As to the cause? We don’t yet know, but Dr. Fong has a theory.

“The reason for retinal vasculitis is unclear,” he said, “but it is probably an immune mediated reaction to the drug and that is the possible reason for delayed appearance of this side effect after 6 months.” One interesting note the ReST committee pointed to is that brolucizumab and aflibercept share roughly the same risk of vision loss over time: 7.4% and 7.7%, respectively. The ASRS report does not indicate what causes said vision loss; just that it occurs.

Novartis stock took a significant hit in February and into March, though the drop was concurrent with wider market trends. It has since clawed back around half of its losses and share prices have been essentially steady between April and June, as of this writing.

With millions of patients being treated for wet AMD, doctors will need to take note of any updated information regarding Beovu. Retinal vasculitis has not been reported as a result of the other current, popular drugs, so their use will likely continue. Patients who were hoping for a reduced injection regimen may have to put up with the current rate of injections — unless they and their doctor decide going off the reservation is worth the risk.

Contributing Doctor

Consultant Vitreoretinal

Surgeon Dr. Kenneth Fong, MA MB BChir (Cambridge),

FRCOphth (UK), FRANZCO (Aust), CCT (UK), AM (Mal), is recognized as an ophthalmologist in the UK, Australia and Malaysia. He graduated with a medical degree from the University of Cambridge in 1998 and trained to be an eye surgeon in London. Dr. Fong then spent two more years training in the UK and at the Royal Perth Hospital in Australia to subspecialize in retina. After 18 years of working in the UK and Australia, he returned to Malaysia in 2009 to serve as associate professor and consultant ophthalmologist and retinal surgeon at the University of Malaya in Kuala Lumpur. He is currently the managing director of OasisEye Specialists in Kuala Lumpur. Dr. Fong is the president of the Malaysian Society of Ophthalmology and serves as a council member for the Asia Pacific Vitreoretinal Society.

kcsfong@gmail.com

with the PIE Radio Show

Ophthalmologists Discuss Important Topics in Vitreoretina

by Brooke Herron

At PIE, we’re sometimes known as the “shock jocks” of ophthalmic publishing — thanks to our funky style (in both fashion and medical reporting). So, we decided to try on those radio show shoes, with a segment of our own: the PIE Radio Show.

We asked renowned surgeons from around the world to chime in on some of the most important topics in ophthalmology today — from COVID-19’s impacts, to business decisions and innovations in medical and surgical retina. So, sit back, relax and don’t touch that dial . . . the PIE Radio Show is ON AIR!

Dr. Diva Kant Misra

Lucknow, India

Vitreoretinal Consultant at Eye-Q Super Speciality Eye Hospital Song Request: “Believer” by Imagine Dragons

Dr. Anil Arora

Sydney, Australia

Ophthalmic Surgeon for Central Coast Eye Specialists and Medical Director of the Laser Vision Clinic Central Coast Song Request: “I Can See Clearly Now” by Johnny Mathis

Dr. Kenneth Fong

Kuala Lumpur, Malaysia

Consultant Vitreoretinal Surgeon and Managing Director of OasisEye Specialists

Dr. Gemmy Cheung

Singapore, Singapore

Deputy Head and Senior Consultant of Medical Retina at Singapore National Eye Centre (SNEC)

Dr. Chirag Shah

Boston, USA

Vitreoretinal Surgeon at Ophthalmic Consultants of Boston and Co-Director of the Tufts/OCB Vitreoretinal Surgery Fellowship

That’s enough, COVID-19

I don’t know about you, but we have coronavirus fatigue here at PIE. Unfortunately, until a vaccine is developed or the virus is somehow contained, it’s going to be hanging around — like an uninvited dinner guest. Worldwide, we are learning to live with it: People are making lifestyle changes to ensure their safety and that of others. And not to sound like a broken record, but COVID-19 has undoubtedly affected ophthalmology — including patients, doctors, staff, clinics, hospitals, equipment and device companies . . . the list goes on. So, what’s happening now that practices are reopening and doctors are seeing patients again?

PIE: Have you noticed any patients with vision loss or disease progression following reopening from the pandemic due to missed treatment?

Dr. Diva Kant Misra: Yes, a lot of patients could not get immediate care for urgent retinal conditions like retinal detachment. In such patients, even minor delays can lead to a poorer visual prognosis. A few of my patients from other cities were able to reach me after considerable hardship and delay. Thankfully we were able to salvage

these eyes, but I had a CRAO (central retinal artery occlusion) patient who came to me after one month, and by that time it was too late for him.

Dr. Anil Arora: I have, unfortunately, had four or five patients who have had worsening of their exudative macular degeneration because they have not kept their appointment for intravitreal anti-VEGF injections. Some patients have been too frightened to come out and some patients (who were residents of nursing homes) were told that if they left their premises, they would have to self-isolate for two weeks upon returning and they did not want to go through that. Fortunately, the decline in vision was not marked in any of these patients and hopefully vision will recover with resumption of regular treatment.

Dr. Kenneth Fong: Yes, there have been a few patients with AMD (agerelated macular degeneration) who lost vision due to the lockdown as they were unable to attend the clinic for their usual injections.

Dr. Gemmy Cheung: During the month of May 2020, about 25% of patients who have active disease in our unit did not attend their appointments. When our team called up this group of patients, about 40% reported that the main reason for not attending their appointment was fear of getting infected. About 90% of patients reported their subjective vision is stable. For the 10% who reported subjective worsening, they agreed to attend the urgent appointment which we re-scheduled to evaluate their condition and reinstate their injections if indicated.

Dr. Chirag Shah: Unfortunately, two patients developed significant submacular hemorrhages and associated visual loss due to missed intravitreal anti-VEGF injections. Further, delayed macular hole surgeries resulted in larger macular holes and reduced visual potential after repair.

PIE: It’s unfortunate to hear that some patients have lost vision during lockdown. Do you think anything in ophthalmology will permanently change as a result of coronavirus? Dr. Fong: The levels of hygiene will improve significantly in all health care institutions and this will benefit staff and patients in reducing the risk of infectious diseases. Within a few months, the whole world will be used to the idea of universal mask use and social distancing.

PIE: Right, so moving forward it seems like there will be extra caution . . . with everything.

Dr. Misra: We are switching to telemedicine, practicing social distancing — and most of all; we see and meet patients from behind the mask. This definitely is going to hamper the patient-doctor connection. It’s ironic that you may not even know the face of the person you trust your eye with. But such are the times, and such is life. We have to do the best with what we have.

Dr. Shah: Coronavirus will likely have many lasting effects on our field. Prior to coronavirus, private equity was spreading throughout ophthalmology practices in the United States, benefitting senior partners at the expense of junior and all future partners. What a stark contrast to the effects of our current pandemic. Now, with uncertainties in revenue and profitability of ophthalmology practices, as well as with volatility in public markets, we may witness a regression of private equity takeovers.

PIE: You’re right, the virus hasn’t only created safety concerns — it’s hit all aspects of the business . . .

Dr. Shah: Yes, and with regard to changes in individual practice, it is possible that those who can work remotely, like administrative assistants and call center staff will continue to do so. Telehealth might also become part of the fabric, particularly for external disease. Sadly, I think many of us will have to retire our tie collection, as ties can serve as a fomite for infectious diseases. Same goes for white coats.

Dr. Anil Arora: I don’t think that anything will change permanently. There will be temporary changes, as are already taking place, which will continue — such as the wearing of masks and goggles; having shields and screens over slit-lamps; reducing clinic bookings; reducing the number of chairs in the waiting room (to keep waiting rooms less crowded); and sanitizing hands and equipment between patients. As restrictions ease, and hopefully as the disease is contained, I think there will be a tendency for things to return to how they were pre-coronavirus.

PIE: These are all valid points — and it will be interesting to see how the lasting effects of COVID-19 play out in ophthalmology. Speaking of the pandemic, are there any questions about it that you’re tired of answering?

Dr. Fong: None, as the situation seems to change weekly, my answers to the same questions are also changing weekly. For example: risk of infection spread caused by aerosolization during cataract surgery; the PPE requirements are not clear yet so I am wearing an N95 mask for all my surgeries, but I do not use a face shield or cover the surgical field excessively.

Dr. Misra: People keep asking about the “new normal.” I am as clueless as anyone else. These are unprecedented times and it will be very difficult to predict how the situation will further develop.

Dr. Shah: None.

Dr. Arora: There is one question and one comment that I have heard frequently that has become a little tiresome. The question is: “When will there be a vaccine for coronavirus?” Everyone seems to have an opinion on this, with projections ranging from later this year to never. I have no idea when there will be a vaccine. There is still no vaccine for HIV or hepatitis-C, so it may be that there will never be a vaccine for COVID-19.

The comment that is tiring after some time is: “Things will never be the same again.” I think that there is always a tendency for people to return to old habits and once restrictions ease — and particularly as domestic and international travel resumes — things will be the same as they were before.

The two things that the coronavirus restrictions have taught me is that we can all do with less than we think, and

that we need to respect Mother Nature. I tend to view viral pandemics as nature’s way of trying to restore the balance when one species becomes too powerful and disrupts that balance. I hope that I and others will continue to remember this as life returns to normal.

Show me the money: Business decisions

In addition to affecting patients and individual practices, the pandemic has also hit the industry’s ophthalmic device and equipment companies — many of whom, like small and medium-sized enterprises (SMEs), may be struggling to stay afloat as demand dries up.

PIE: Are you, or is your clinic/ hospital planning to purchase any new equipment or devices in 2020? In 2021? And if so, what?

Dr. Misra: All planned purchases have been stalled for the moment. We are evaluating the rapidly changing scenario and will reconsider those purchase decisions after everything stabilizes.

Dr. Arora: We have recently upgraded to the ZEISS CIRRUS 6000 model of optical coherence tomography (OCT). We have purchased two of these and are particularly enjoying the rapid image acquisition speed, along with several other new features. We are also looking at purchasing the CLARUS widefield fundus imaging system (from ZEISS) in the coming year.

Dr. Fong: No, due to a reduction in workload caused by the pandemic and lack of budget.

Dr. Shah: My practice bought scrubs for all of the staff in an effort to provide clothing that would be washed after a day of work to minimize the spread of coronavirus. They also plan to buy an intense pulsed light (IPL) laser for dry eye treatment.

Vitreoretinal hits: What’s topping the charts?

Moving on, technology and treatments for posterior segment conditions are constantly evolving. Let’s talk about that. . .

PIE: Are there any innovations in the development pipeline that you’re following closely in surgical? In medical?

Dr. Misra: I am closely observing the developments in the field of bionic eyes and related research.

Dr. Fong: 3D visualization systems will be helpful as they will not require surgeons to be so close to the surgical field — and they could also potentially reduce occupational related neck and back pain.

Dr. Arora: In medical, I am looking forward to seeing the introduction of brolucizumab (Beovu; Novartis, Basel, Switzerland) in Australia for the treatment of exudative age-related macular degeneration (AMD). I have not used it myself, but if it can reduce the frequency of intravitreal injections from monthly — as is typically the case now — to every three to four months as the company claims, it will greatly reduce the burden of treatment for ophthalmologists . . . and hopefully, reduce the massive cost that intravitreal injections have on the health system in many countries.

I am aware of reports and concerns about it [Beovu] producing occlusive retinal vasculitis. These have occurred in the U.S. following approval of the drug for wet AMD and were not present (or at least not with anywhere near the same frequency) in the clinical trials preceding approval. There may be an immune response and apparently some treatment naive patients have antibodies to Beovu. The company is addressing these concerns and hopefully, if they are resolved, we will have a new medication in our arsenal to manage AMD more effectively.

In surgical, having become comfortable with 25-gauge vitrectomy for almost all vitreoretinal procedures, I look forward to making the transition to 27-gauge vitreoretinal surgery in the near future. It is amazing to think that we can do vitreoretinal surgery and procedures such as laser photocoagulation, silicone oil injection and membrane peeling, through openings that are the same size as a needle used by diabetics to administer insulin.

Dr. Shah: Stem cell transplantation for atrophic AMD is always an intriguing topic to help stabilize — or even restore some vision — in patients with a presently blinding condition. If approved, I do wonder how operating rooms will be able to accommodate the surgical volume if transplantation requires vitrectomy with subretinal delivery.

PIE: Indeed, these new treatments and devices certainly sound both interesting and promising. Building on that, what do you think is the most important topic in vitreoretina today? Or is there a topic that you feel deserves more attention?

Dr. Arora: I’m not sure I can single out one topic as being the most important. I think if you ask 10 different ophthalmologists you may get 10 different answers. Perhaps the condition that is most in need of a treatment is dry (or atrophic) AMD. While we now have a variety of intravitreal agents for wet AMD, there are still no really good answers for the dry form.

Dr. Fong: We need longer acting drugs or depot devices to deliver treatments for AMD, diabetic macular edema (DME) and retinal vein occlusion (RVO). The pandemic has shown that we need to reduce our retina patient visits without compromising on their vision. Current anti-VEGF agents only allow, at most, three monthly intervals between visits for a small number of patients. Most patients still need to come back monthly.

Dr. Misra: I feel the role of artificial intelligence in battling diabetic retinopathy blindness will be a game changer in a country like India.

Dr. Shah: At the moment, it is most imperative to keep our elderly, the most vulnerable patients, safe in our offices. This requires careful consideration of all the steps patients take during a typical office visit so that we can maximize the efficiency of the visit to minimize risks associated with patients congregating in the waiting room. This may also require a reevaluation of the patient scheduling, possibly stretching out the day and reducing the number of patients per hour.

PIE: It sounds promising that there are some devices and treatments in the R&D pipeline to address some of these sight-threatening retinal diseases. Furthermore, as the pandemic continues, it’s clear that continued vigilance will be required to not only keep patients safe, but to keep businesses running.

Well, looks like we’re out of time . . . we appreciate all the “callers” who “phoned-in” to the inaugural PIE Radio Show. Until next time…

Editor’s Note:

Answers to these questions were submitted via email by the surgeons interviewed. Responses have been edited for length and clarity, and edited into a Radio Show transcript. And while the PIE Radio Show did not occur in real time, the answers are real.

Contributing Doctors

Dr. Diva Kant Misra completed his vitreoretinal surgery fellowship from Sri Sankaradeva Nethralaya. He holds the post of general secretary for the Young Ophthalmologists Society of India and chief editor for the Young Ophthalmologists Times. He is the recipient of various Ophthalmic awards like the APAO Achievement Award, Bangkok 2019; Best of IJO Award 2017-18; Ophthalmic Hero of India 2017 & 2018; KOS International Travel Grant 2019, Busan; the Yasuo Tano Award from Asia Pacific Academy of Ophthalmology, Singapore 2017; and the APVRS Tano Award 2018, Malaysia; and other national & state level awards. He has published extensively (26 publications and book chapters) and has presented in conferences held at various international and national forums and has been an invited faculty in international forums like EURETINA, APAO and AAO.

divakant@gmail.com

Dr. Kenneth Fong is recognized as an ophthalmologist in the U.K. ,Australia and Malaysia. He graduated with a medical degree from the University of Cambridge in 1998 and trained to be an eye surgeon in London. Dr. Fong then spent two more years training in the UK and at the Royal Perth Hospital in Australia to subspecialize in retina. After 18 years of working in the UK and Australia, he returned to Malaysia in 2009 to serve as associate professor and consultant ophthalmologist and retinal surgeon at the University of Malaya in Kuala Lumpur. He is currently the managing director of OasisEye Specialists in Kuala Lumpur. Dr. Fong is the president of the Malaysian Society of Ophthalmology and serves as a council member for the Asia Pacific Vitreo-retinal Society.

kcsfong@gmail.com

Dr. Anil Arora is an ophthalmologist practicing in the Central Coast and in Sydney since 1998. He completed his medical degree through the University of Sydney in 1985 and after carrying out his internship and residency training at Royal North Shore, Westmead and Royal Prince Alfred Hospitals, he embarked on a career in ophthalmology. He is a Fellow of the Royal Australian and New Zealand College of Ophthalmologists (RANZCO), American Academy of Ophthalmology (AAO) and American Society of Cataract and Refractive Surgery (ASCRS). Clinical interests include cataract surgery, particularly with multifocal intraocular lenses, retinal diseases and surgery, and laser refractive surgery. He also has an interest in ophthalmology in developing countries and in charity work: Dr. Arora sponsors 60 children in all parts of the world through World Vision and has been a member of Amnesty International for over 10 years.

anilarora1@hotmail.com

Dr. Chirag Shah is a vitreoretinal surgeon at Ophthalmic Consultants of Boston and codDirector of the Tufts/OCB Vitreoretinal Surgery Fellowship. He is the section editor of the Clinical Trials section of Retina Times, and serves as a sub-investigator on numerous clinical trials. He recently co-authored Financial Freedom Rx: The Physician’s Guide to Financial Independence, which should be in press in 2021.

cpshah@eyeboston.com

Dr. Gemmy Cheung currently serves as deputy head and senior consultant of the medial retina service for Singapore National Eye Centre (SNEC), as well as senior clinician investigator for the Singapore Eye Research Institute (SERI). Her research interests include the study of risk factors and clinical features of macular diseases that may be unique in Asian populations. Dr. Cheung has published more than 150 articles, mostly regarding age-related macular degeneration, including polypoidal choroidal vasculopathy, and conducted several clinical trials in anti-vascular endothelial growth factor therapies. Dr. Cheung has also been actively involved in training and education, and has served as an instructor on Asia-Pacific Academy of Ophthalmology (APAO) and American Academy of Ophthalmology (AAO) courses and many other educational programs. In addition, she is also a volunteer faculty member for the ORBIS Flying Eye Hospital Programme. Dr. Cheung has received a number of prestigious awards, including the Macula Society Young Investigator Award (2017), APAO achievement award (2017), APAO Nakajima Award (2014), APAO Outstanding Service in Prevention of Blindness Award (2013), the Bayer Global Ophthalmology Research Award (2012), the Roper-Hall Medal (2005) and the Elizabeth Hunt Medal (Royal College of Ophthalmologists, UK).

gemmy.cheung.c.m@singhealth. com.sg

From Da Nang, Vietnam tothe World Q&A from Quarantine

As the coronavirus traversed the globe, countries around the world imposed social distancing and shelter-in-place orders (with various levels of restrictions) on their citizens. During this time, all but essential services came to a standstill, including non-emergency and elective ophthalmic procedures. How did surgeons and industry professionals cope — and continue to learn, network and share information — during the pandemic?

To learn more — and as part of PIE and CAKE magazines’ continuing coverage of the COVID-19 pandemic and its impact on ophthalmology — CEO Matt Young, in Da Nang, Vietnam interviewed KOLs from around the world. Here are some of those connections . . .

Be sure to check out all the videos in the video section of our new websites cakemagazine.org and piemagazine.org.

EUROPE >>> 1

Dr. Mario Romano

Director of the Ophthalmology Department at Humanitas Gavazenn Bergamo, Italy

6

Mr. Alessio David

Business Development Manager, Alfa Intes Industria Terapeutica Splendore Napoli, Italy

7

Dr. Paisan Ruamviboonsuk

Assistant Director of the Centre of Medical Excellence at Rajavithi Hospital Bangkok, Thailand

2

Mr. Adel Bencheikh

Director, Eye Care Division at Canon Medical Systems Europe B. V. Zoetermeer, The Netherlands

5

Mr. Frederic Giulj

Export Manager at Moria SA Montrouge, Île-de-France, France

8

Dr. Kenneth Fong

Managing Director of OasisEye Specialists, Congress President, The 36th Congress of APAO (APAO 2021) Kuala Lumpur, Malaysia

3

Dr. Rafiq Hasan

Former Vice-President and Global Head of Ophthalmology at Bayer Basel, Switzerland

4

Dr. Luis Diaz-Santana

Head of Ophthalmology at Cambridge Consultants Cambridge, United Kingdom

9

Dr. Arun Sethi

Arunodaya Deseret Eye Hospital Gurugram, India

10

Mr. Franck Morand

Vice President for Asia-Pacific at Quantel Medical Chiang Mai, Thailand

15

Dr. Adrienne Graves

Corporate Board member; Independent Director; Chair of Compensation and Governance Committees North Carolina, USA

11

Mr. Jim Mazzo

Adviser and Consultant for Carl Zeiss Meditec Dublin, California, USA

14

Mr. Thomas Dunlap

Ophthalmic Medical Device Consultant Orange County, California, USA

16

Dr. Igor Kozak

Vitreoretinal Surgeon at Moorfields Eye Hospital Center Abu Dhabi, United Arab Emirates (UAE)

12

Mr. Armond Dantino

Senior Vice President of International Sales for MacuLogix Pensacola, Florida, USA

13

Mr. Alex Bergoudian

Vice President of Sales at Katalyst Surgical St. Louis, Missouri, USA