I started my ophthalmology training in 1965 at Ghent University, Ghent, Belgium, in the department of Prof. Jules François, who was a man of many talents (author or co-author of 1,870 peer-reviewed articles; doctor honoris causa at 21 universities) and a very didactic teacher!

Later, I founded the Ghent University clinic department of ultrasound, where I stayed some 15 years as a consultant. In 1968 I started my private practice in Antwerp, Belgium, as a solo practitioner.

I have had the privilege to be a spectator, often a participant and sometimes a leader in the most important developments in ophthalmology over the 50-plus years since I started my ophthalmology career. It is my honour to share the most important learnings and developments with the reader.

Most of these happened during the first 30 years of my career in ophthalmology. Indeed, except for the introduction of intravitreal anti-vascular endothelial growth factor injections, there have been no spectacular advancements in ophthalmology since then.

I observed, during those first 30 years, the birth of the IOL,the introduction of phaco-emulsification techniques and the use of lasers in the treatment of eye diseases and in refractive eye surgery. Vitreoretinal surgery has boomed and modern eye examination methods (OCT, retinal scans, topographic modelling) have improved and now help in making better diagnoses.

During my first years in ophthalmology, we worked with a head loupe(with a 6x magnification) and had to open the eye for cataract surgery with a von Graefeknife over 145°, remove the cataract with forceps and close the corneal wound with eight 6-0 silk sutures. The patient stayed in hospital for 5 days and recuperation of normal vision, after removal of the stitches and prescription of the very high hyperopic lens, took 7 weeks.

Thedevelopment of the artificial IOL—first implanted by the late Sir Harold Ridley at St Thomas’ Hospital in London in February 1950—changed the course of cataract surgery. However, it took several years before Ridley’s invention became widely accepted; I performed my first lens implant in the late 1970s. Before then, it made no sense to perform unilateral cataract surgery.

Indeed, the obligatory use of the very disturbing postoperative aphakic correction was only supported when used bilaterally. These high hyperopic(+12 D)glasses caused a 25% magnification of the image, which was not supported when prescribed unilaterally. These ugly glasses were also responsible for the very annoying roving ring scotoma called the “jack in the box phenomenon,” which made driving a car a very risky business.

Only when contact lenses for the correction of aphakia were introduced, towards the end of the 1970s, did it make sense to operate unilaterally, as the contact lenses created a magnification of only 6–8% and this difference could be supported by the other phakic eye.

Once phacoemulsification became available, after the late Charlie Kelman’s discovery in 1967, the corneal opening needed only to be 5 mm and then, after the introduction of foldable implants, 3 mm. Stitches were no longer needed because a scleral tunnel approach was already in use before foldable lenses became available.

In 1987 I mastered the technique during a course given by Dr Jim Little, an associate of Kelman, in Geneva, Switzerland. At that time there were only four surgeons in Belgium using this method. I recall that in the United States some time later, a wet lab on pig and rabbit eyes was organised in the ballroom of the Hilton Hotel. One hour later, a wedding party was held in the same room!

IOLs improved progressively over time. Tinted and UV-coated lenses became available and, from around 1990, presbyopia-correcting lenses(bifocal, trifocal and so-called accommodative lenses) were introduced.

The evolution continued and I became involved in many studies on foldable IOLs (Tecnis) and presbyopia-correcting lenses, and lectured on them at European and American meetings. The most difficult part was selecting the right patient for the right lens.

The use of phakic IOL implantations in myopia and hyperopia became important in refractive surgery.Lenses included the Artisan lens, an iris-fixated lens first launched for cataract surgery and later also used for myopia and hyperopia correction in phakic eyes; the Verisyse IOL; and the Veriflex, which is the foldable IOL; all designed by Jan Worstfrom the early 1980s onwards.

The Artisanwas initially referred to as the “worst” lens and so this was a difficult one to promote! I used to perform the surgery bilaterally in one session under topical anaesthesia so that the patient immediately obtained an excellent result. These surgeries gave me the most satisfaction.

This technique, now used in every modern cataract surgery procedure, was unknown when I performed my first cataract surgeries. It was popularised simultaneously by Dr Howard Gimbel in Calgary, Alberta, Canada, and Prof. Thomas Neuhann in Munich, Germany, in 1983–1985, both of whom went on to publish their work in 1991.

I visited the two ophthalmologists, acquired the technique and have excellent memories of working with them during many American Academy of Ophthalmology (AAO) and American Society of Cataract and Refractive Surgery (ASCRS) courses.

The use of aburied corneal knot when stitching up corneal wounds was also unheard of when I started cataract surgery. This technique, whereby the corneal silk stitches knot is reversed and buried in the stroma, was introduced in France by Dr Jacques Charleux in the 1970s.

Before this, the surgeon had to cut the stitches very short so that they did not cause too much irritation, which is difficult to imagine. Of course, nowadays, in most cataract surgeries the incision is so small that stitches are unnecessary.

Cataract surgery in a freestanding centrewas undertaken for the first time in Arizona, US, in the 1970s, being unknown in Europe at that time.Of course I wanted to apply these new approaches in my practice: in 1984 I realised the first cataract surgery on an outpatient basis in the Benelux region (Belgium-Netherlands-Luxemburg) in my clinic in Antwerp.

Nowadays, a maximum error of 0.25 in the outcome of IOL power calculation seems achievable, but this was not always so. Ridley’s first two cases resulted in an important postoperative refractive error because the refractive power of the material used was unknown and the importance of eye-length measurement had still to be discovered.

IOL power calculation formulas were progressively developed and improved. As American ophthalmologist Prof. Jack Holladay once said, surgeons have the best outcomes with their own formulas.

Measurement techniques have improved spectacularly from the starting point of a contact method that used A-scan biometry, applying a contact probe on the eye with the risk of causing an eye deformity, implementing anatomical instead of optical biometry and creating inaccuracies.

At Ghent University in the late 1970s, together with Dr Roger Allewaert, we developed one of the first optical biometry calculation programs. Optical biometry using the Zeiss IOL master appeared in the late 1990s and I later became involved in teaching many courses on this subject.

When I started working in ophthalmology there were no important congresses in Europe, although there were a few very famous professors working in France, Germany, Italy and Belgium. Meetings were more social gatherings than scientific sessions; wet lab and video courses were non-existent and those interested in learning about the latest developments in ophthalmology and meeting pioneers in the field had to visit the US and attend the AAO or the ACS (later ASCRS) meeting.

It was in the US that I learned about outpatient cataract surgery, radial keratotomy, lens implants and phaco surgery, as well as peribulbar(Drs David Davis and Mark Mandel, 1985) and, later, topical anaesthesia (Dr Richard A. Fichman, 1991). The European congresses(for example, European Society of Ophthalmology and European Society of Cataract and Refractive Surgeons) gradually became more important and began to compete successfully with the American congresses.

Botulinum toxin for the treatment of strabismus was introduced by the late Alan Scott in 1973. When I started using botulinum toxin type A for the treatment of blepharospasm in 1980, the condition was still considered a psychiatric disease. At that time I had no idea that this treatment would become so widespread for so many other medical conditions as well as for cosmetic reasons.

After I had met Scott at one of the AAO meetings, I was able to order the product overseas. It was delivered in a protected lead container because one such a shipment could have killed a huge proportion of the citizens of Antwerp! The dry product was dissolved, diluted one million times and made ready for injection by our pharmacist.

The product received US Food and Drug Administration (FDA) approval for strabismus and blepharospasm in 1989, and in 2002 it received FDA approval for the cosmetic applications as ‘Botox’ (Allergan).

In 1970, Svyatoslav Nikolayevich Fyodorov (1927–2000), a surgicalpioneer, wasthe first to discover that the curvature of the cornea, and consequently its refractive power, changed after it had been perforated by a traumatic impact.This was the start of radial keratotomy whereby 8–16 or sometimes 32 radial incisions were used to flatten the cornea, reducing myopia. This treatment was brought to the US by Leo Bores in the late 1970s.

I attended some courses during weekends in the US, then flew back to Europe and started practising the technique, but first I tested the extremely sharp diamond knife on rabbit eyes. I incised their corneas then placed the rabbits in my mother’s garden and checked on them the next morning.

I found that they were happilyjumping around and eating as if nothing had happened. This was proof for me that I had mastered the technique and could start operating on human patients.

In 1985, I became acquainted with the first application of the excimer laser for refractive surgery. Eight European surgeons attended a session in Wangen, Germany, whereit was demonstrated how the excimer laser (MEL 50) could improve the making of radial incisions.

Dr Stephen Trokel, who is regarded as being the first ophthalmologist to recognise the significance of the excimer laser for use in corneal refractive surgery,was present.He had flown in that morning and was extremely tired, falling asleep during the evening dinner.

We later realised that the incision approach was not the right one and that removing part of the cornea was a much better way. In 1992,after a European meeting in Brussels, I organised the first live refractive laser surgery with an excimer laser.

This had never been done before anywhere in the world, but I did not realise that until later. Nearly all European and many American surgeons who were later to become famous in the discipline of laser refractive surgery were in attendance. Together with Prof. Dieter Dausch and some pioneers of excimer laser refractive surgery (members of the Carl Zeiss Academy), and later on Prof. Dan Reinstein, we lectured worldwide on the use of the excimer laser in ophthalmic refractive surgery.

At first we used the rather brutal technique of PRK, whereby the corneal epithelium was removed before the application of the laser. Healing took 3 days and was very painful. The use of a bandage contact lens relieved the pain and the switch to LASIK made it possible to treat both eyes in the same session and practically without pain. Later on, the femtosecond laser was introduced in my eye centre.

I was fortunate to have been involved in the first discussions, at the Zeiss Academy group in Barcelona, Spain, in 2008, where the idea of femtosecond lenticule extraction with a flap (FLEx) and, later on, SMILE was developed. “Mr SMILE,” Prof. Walter Sekundo, was at the forefront of this development.

Nobody at that time could have foreseen that refractive laser eye surgery would become the second most-performed surgery on the human body, after cataract surgery.

Other lasers (argon and krypton lasers) featured in ophthalmic treatmentfrom 1970 onwards. Specifically, the introduction of the Nd-YAG laser after 1980 created a revolution in the treatment of posterior capsule opacification.Until then, this complication had had to be treated by a surgical incision of the opacified capsule.

My ultimate hope is that my colleagues experience still more improvements in the beautiful discipline of ophthalmology and that all patients have the possibility of accessing timely and speedy access to the eyecare they need.

Dr Goes is the founder of the Goes Eye Center in Antwerp, Belgium (www.drgoes.be), and is still active as a consultant at the centre. He has no relevant financial disclosures.

Articles

Dr Goes reflects on a life at the forefront of ophthalmology, considering advancements in technology and the knowledge that has changed his practice and improved outcomes for patients.

Half a century of developments in ophthalmology: One doctor’s reflections

Tarsus Pharmaceuticals, Inc. today announced positive topline results of TP-03, which met the primary endpoint and all secondary endpoints, in the Saturn-2 Phase 3 trial with a favourable safety profile, reinforcing its ability to treat 

 blepharitis. With these positive results, Tarsus plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second half of 2022, according to a press release.

“The positive Saturn-2 data builds on the compelling results we observed in Saturn-1, demonstrating clear consistency in the safety, efficacy and strong clinical value proposition of TP-03. This milestone enables a first potential treatment for 

blepharitis and most importantly, provides hope to the millions of patients suffering from this disease,” Dr Bobak Azamian, president and chief executive officer of Tarsus, said in the release.

“As we direct our focus toward NDA filing and commercialization, we are one step closer to providing a solution to eye care professionals and patients that can resolve this disease," Dr Azamian said.

“We are truly grateful to the many patients who participated in the trial and appreciate their time and commitment despite the challenges presented by the ongoing COVID-19 pandemic," continued Dr Azamian. "We are also sincerely thankful for the investigators and our clinical team who skilfully drove the execution of this successful trial. We’re thrilled to move the regulatory path forward for TP-03, which – if approved by the FDA – will potentially establish a definitive standard of care for 

blepharitis and benefit as many as 25 million U.S. patients in need.”

 blepharitis is the most common ectoparasite found on humans and may affect as many as 25 million Americans, according to the release. Currently, there are no FDA-approved treatments for 

TP-03 (lotilaner ophthalmic solution, 0.25%) is Tarsus’ novel, investigational therapeutic designed to resolve 

“The high statistical significance and clinically meaningful outcomes in Saturn-2 and Saturn-1 demonstrate the impressive ability of TP-03 to resolve 

blepharitis, a disease that has long been without an effective, safe treatment option,” said Elizabeth Yeu, M.D., Director and Chief Medical Advisor for Tarsus. “We know that this disease has a significant impact on patients’ vision and their daily life, and that they often struggle for years without relief. I am thrilled at the prospect of having TP-03 potentially available in the near future.”

Saturn-2 is a Phase 3 randomized, controlled, double-masked trial evaluating the efficacy and safety of TP-03 in patients with 

blepharitis. The trial enrolled 412 adults having more than 10 collarettes per lid and at least mild lid erythema (redness), with at least 1.5 mites per lash. One drop of TP-03 was self-administered twice per day in each eye for six weeks. Enrolled patients received no treatment for blepharitis (e.g., lid hygiene) during the trial or 14 days prior to enrolment.

Key topline results, as stated in the release:

Complete collarette cure, defined as 0 to 2 collarettes per lid at day 43, was achieved by 56% of patients on TP-03, compared to 13% on vehicle (

Additionally, 89% of patients achieved a significant, clinically meaningful collarette cure defined by a collarette grade of zero (0) or one (1) at day 43 compared to 33% of those on vehicle (

: Defined as a mite density of zero (0) mites per lash, was achieved by 52% of patients on TP-03 compared to 14% on vehicle (p<0.0001) at day 43.

 31.1% of patients on TP-03 compared to 9.0% of patients on vehicle (

 < 0.0001) achieved a complete lid erythema cure at day 43.

 19.2% of patients on TP-03 achieved a complete composite cure, based on achieving both collarette cure and erythema cure, compared to 4.0% on vehicle (

Consistent with Saturn-1, Saturn-2 trial results demonstrated that TP-03 was well-tolerated with a safety profile similar to the vehicle group.

91% of patients reported that the drop comfort was neutral to very comfortable.

There were no serious treatment-related adverse events. The only adverse events occurring at a rate of ≥ 1% in the TP-03 group were instillation site pain/burning/stinging (7.9%, n = 16) and dry eye (1.5%, n = 3).

According to the release, TP-03 was evaluated in two pivotal trials collectively involving 833 patients. Both trials met the primary and all secondary endpoints, with statistical significance and no serious treatment-related adverse events. Both trials also demonstrated that TP-03 was generally safe and well-tolerated. If approved, TP-03 may offer treatment for millions of patients with 

TP-03 met the primary and all secondary endpoints, effectively resolved Demodex blepharitis and was well-tolerated with no serious treatment-related adverse events. 56% of patients on TP-03 achieved the primary endpoint of complete collarette cure.

Positive topline data from Saturn-2 Phase 3 trial encourages Tarsus to file NDA in 2022

Skye Bioscience Inc. this week announced the release of preclinical data

 demonstrating stronger and longer-lasting reduction of intraocular pressure (IOP) when Skye’s proprietary molecule, SBI-100, is formulated as a nanoemulsion containing the mucoadhesive agent Carbopol 940.

In a news release, Skye, in collaboration with investigators at the University of Mississippi, previously published preclinical data

 demonstrating SBI-100 formulated as a nanoemulsion (THC-VHS-NE) achieved greater reduction of intraocular pressure in non-pigmented rabbits than both latanoprost and timilol, the current first and second line treatments for glaucoma, respectively. The current study was undertaken to determine if the inclusion of a mucoadhesive agent could prolong the intensity and duration of action of the THC-VHS-NE formulation through increased residence time or penetration, or both, to potentially achieve once- or twice- a day dosing.

According to the release, in this study sponsored by Skye, researchers at the University of Mississippi compared the reduction of IOP in normotensive rabbits with a single treatment of THC-VHS-NEC (SBI-100 formulated as a nanoemulsion with Carbopol 940) compared to latanoprost, the commercial standard of care; THC-NEC (native THC formulated as a nanoemulsion with Carbopol 940); and THC-VHS-NE (SBI-100 formulated as just a nanoemulsion). When comparing each treatment group, THC-VHS-NEC, Skye’s SBI-100 ophthalmic emulsion, demonstrated the greatest intensity and duration of IOP-lowering.

Punit Dhillon, CEO and chairman of Skye, noted in the news release that the company has been working aggressively to optimize a formulation of SBI-100 to advance toward a first in-human study, which is planned to start this quarter.

“We previously reported strong preclinical results that highlighted the superior IOP-lowering of our unique molecule formulated as just a nanoemulsion compared to other established commercial glaucoma drugs,” Dhillon said in the release. “This further evolution of our formulation, generating even more robust results, gives us strong conviction as we step into the clinic with SBI-100 ophthalmic emulsion.”

Dhillon added that the company’s goal with this program is to advance a new class of glaucoma treatment with a once or twice a day dosing regimen.

“Positive, prior third-party research relevant to our molecule and this preclinical work informed our selection of the best formulation of SBI-100 for this application,” Dhillon concluded.

In comparison to THC-VHS-NE, THC-NEC and commercial latanoprost, THC-VHS-NEC (SBI-100 ophthalmic emulsion) exhibited a prolonged duration of action. THC-NEC and THC-VHS-NE formulations respectively produced an average maximum drop in IOP of 3.7 mm Hg at 60 minutes and 4.8 mm Hg at 150 minutes, while the IOP-lowering effect lasted for 240 and 360 minutes, respectively, in the treated eye. In contrast, SBI-100 ophthalmic emulsion lowered IOP by 4.5 mmHg at 60 min and maintained this drop for at least 480 min in the treated eye.

 < 0.05) in IOP-lowering was also observed between SBI-100 Ophthalmic Emulsion and commercial latanoprost ophthalmic solution. The average maximum drop in IOP with SBI-100 ophthalmic emulsion (THC-VHS-NEC) of 4.5 mm Hg at 60 minutes was almost twice that obtained with commercial latanoprost ophthalmic solution (2.3 mm Hg) at 60 minutes.

Moreover, latanoprost maintained IOP 10% below baseline for only 360 minutes, whereas SBI-100 ophthalmic emulsion maintained the IOP- lowering effect for at least 480 min (

1. Sweeney, C., Dudhipala, N., Thakkar, R., et al. Impact of mucoadhesive agent inclusion on the intraocular pressure lowering profile of Δ9-tetrahydrocannabinol-valine-hemisuccinate loaded nanoemulsions in New Zealand white rabbits. Int’l Journal of Pharmaceitics. Published March 25, 2022. https://doi.org/10.1016/j-ijpharm.2022.121564

2. Sweeney, C., Dudhipala, N., Thakkar, R. et al. Effect of surfactant concentration and sterilization process on intraocular pressure–lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (NB1111) nanoemulsions. Drug Deliv. and Transl. Res. 11, 2096–2107 (2021). https://doi.org/10.1007/s13346-020-00871-9

In research sponsored by Skye Bioscience Inc., investigators at the University of Mississippi have demonstrated stronger and longer-lasting reduction of intraocular pressure when a proprietary molecule, SBI-100, is formulated as a nanoemulsion containing the mucoadhesive agent Carbopol 940.

Nanoemulsion formulation enhances IOP reduction, study finds

, sits down with Dr Jennifer I. Lim to discuss her ARVO 2022 presentation, “Efficacy, durability, and safety of faricimab in diabetic macular oedema: 2-year results from the phase 3 YOSEMITE and RHINE trials.” YOSEMITE and RHINE trials had previously shown noninferiority between faricimab and aflibercept for the treatment of diabetic macular oedema (DMO), and the 2-year results showed that up to 60% of patients could be dosed with faricimab every 16 weeks and 70% of patients could be dosed every 12 weeks following 4 loading doses.

Videos

Dr Jennifer I. Lim reviews the 2-year results of the YOSEMITE and RHINE trials, outlining the efficacy, durability, and safety of faricimab in diabetic macular oedema.

2-year YOSEMITE and RHINE results show faricimab reduces treatment burden in patients with DMO

A team of Spanish investigators, led by Dr Eva Chamorro, director of clinical research, and colleagues from Indizen Optical Technologies SL, Madrid, are studying the effects of different spectacle lenses that add different levels of defocus to the peripheral retina to control myopia.

In a poster presented at the Association for Research in Vision and Ophthalmology’s 2022 annual meeting in Denver, Colorado, United States, the investigators noted that the axial length (AL) changes over the course of a day (diurnal rhythms) with imposed defocus. This suggested, they pointed out, that these short-term changes in the AL might predict the efficacy of treatments to control myopia.

With this in mind, they conducted a pilot study to evaluate the effects of different types of myopia control spectacle lenses on the diurnal AL changes in young adults who were either emmetropic or wore contact lenses. The Als were measured in 6 subjects who wore glasses with a myopia control lens that had a plano central region and imposed peripheral defocus over the dominant eye; the fellow non-dominant eye had a plano control lens.

Three different myopia control lenses were used to induce the defocus, specifically, the Miyosmart (Hoya, Kuala Lumpur, Malaysia); Stellest (Essilor, Kuala Lumpur), and a non-commercial prototype (IOT, Madrid). All measurements of the AL were obtained at baseline without the lenses and then performed over 4 consecutive days with the lenses. After the measurements were completed, the investigators analysed the differences both between the control and study eyes with each type of myopia control lens and the differences between baseline and the treatment days in the treated eyes, they described.

The investigators observed a significant increase in the AL between the control and treatment eyes with the Stellest and the noncommercial prototype lenses after 2 hours in the treated eyes. With the Miyosmart lens, they observed non-significant differences between the eyes at all times during the lens use.

The comparison of the AL changes in the treatment eye between baseline and the treatment day showed significant differences with the 3 myopia control lenses, which indicated that the use of all 3 resulted in increases in the AL. Minimal daily changes in the AL, they reported, were seen at baseline that day, with variations of less than 0.01 mm across all time intervals.

“Myopia control spectacle lenses affect the diurnal rhythms in the AL in young adult human and produced a small short-term increase in the AL that varies in intensity and time interval for each of the 3 studied lenses,” Dr Chamorro concluded. “Additional studies with a larger sample size and longer follow-up periods are necessary to confirm that short-term variations of diurnal rhythms can be used as predictor of myopia control efficacy.”

Dr Eva Chamorro points out that myopia control spectacle lenses affect the diurnal rhythms in the AL in young adult human and produced a small short-term increase in the AL that varies in intensity and time interval for each of the 3 studied lenses. 

Testing spectacle lenses for myopia control in relation to changes in axial length

Dr Christina Herrspiegel and colleagues from the Karolinska Institutet and St. Erik Eye Hospital, Stockholm, Sweden, reported that they have developed a prognostic test, referred to as serUM, that they believe is a strong predictor of metastasis of uveal melanoma.

The test is based on serum obtained from peripheral blood samples at the time of diagnosis of uveal melanoma in 83 patients (52% women; mean age at diagnosed, 65 years) from 1996 to 2000 at St. Erik Eye Hospital, they explained. All patients were diagnosed with primary melanoma in the choroid or ciliary body.

The investigators performed both proteome profiling of 84 different cancer-related proteins to screen for potential biomarkers and an enzyme-linked immunosorbent assay to evaluate the serum levels of the best protein candidates. Receiver operating characteristics were used to define thresholds for metastatic risk, they explained.

The prognostic test, serUM, was developed in a training cohort and tested in a validation cohort.

In the study patients, the mean tumour diameter and thickness were, respectively, 9.8 mm and 4.9 mm.

The proteome profiling evaluated 5 proteins, Leptin, Osteopontin, Progranulin, Tenascin C, and DLL-1, for further analysis. The prognostic test was based on the Leptin and Osteopontin concentrations developed in the training cohort (n = 17) and then tested in a validation cohort (n = 62) after exclusion of three patients with unreliable total protein fractions, the authors reported.

The results showed that with each increasing metastatic risk category, the patients had gradually shorter cumulative metastasis-free survival (log rank p for trend = 0.01).

Multivariate Cox regression analysis indicated that serUM was an independent predictor of metastasis when entering all of the following as covariates, the tumor diameter, tumour thickness, and patient age at diagnosis (hazard ratio 2.4, 95% confidence interval, 1.0-5.3).

Dr Herrspiegel and coauthors concluded, “serUM, a prognostic test based on serum obtained from a peripheral blood sample at diagnosis of uveal melanoma, is a strong predictor of metastasis.” They emphasized the need for future prospective studies to validate the findings of the current study.

Investigators from the Karolinska Institutet and St. Erik Eye Hospital, Stockholm, Sweden, reported that they have developed a prognostic test, referred to as serUM, that they believe is a strong predictor of metastasis of uveal melanoma.

Predicting metastasis with novel prognostic liquid biopsy for uveal melanoma

Dr Tine Van Bergen reported the preclinical data from a study of THR-687 (Oxurion NV), a selective RGD integrin antagonist, for treating diabetic macular oedema (DMO). The results showed that THR-687 provides protection against retinal vascular permeability, inflammation and reactive gliosis in a diabetic rat model. Dr Van Bergen is a senior scientist with Oxurion NV.

RGD-binding integrins modulate numerous biological processes including cell differentiation, adhesion, shape, migration, motility, invasion, proliferation and survival. Under pathological conditions, integrins may be aberrantly activated. In the eye, integrins have been shown to play an important role vascular leakage, inflammation, angiogenesis and gliosis. Consequently, integrins have emerged as promising targets for therapeutics development.

Dr Van Bergen and co-workers investigated the potential of THR-687 in the streptozotocin (STZ)-induced diabetic rat model to determine the effects on DMO-related hallmarks. They tested 3 intravitreally injected doses (6.7, 16.7, or 75 µg/eye) of THR-687 or vehicle (control) in both eyes of the animals at intervals of 1 week.

The investigators reported, “THR-687 reduced the diabetes-induced increases in retinal permeability versus vehicle in a dose-dependent manner. Furthermore, all doses of THR-687 also significantly reduced the number of inflammatory cells compared to vehicle. The highest dose of THR-687 reduced the diabetes-induced activation of Müller cells.”

Based on the results, they concluded that THR-687 inhibits vascular permeability, inflammation and gliosis in the diabetic is rat model. In addition, because of its multifaceted mechanism of action, THR-687 may have the potential for a broader biologic effect compared to anti-VEGF therapy.

THR-687 is currently in Phase 2 clinical trial (INTEGRAL - NCT05063734), which consists of a two-part study. Part A aims to select the dose level after multiple injections, while Part B will evaluate the efficacy and safety of the selected THR-687 dose versus aflibercept in treatment-naïve and previously treated DMO patients. The data of Part A study is expected to be released within this quarter.

THR-687 is currently being evaluated in a phase 2 clinical trial in patients with DME. The first data from the dose-optimization study is expected to be released in the first half of 2022.

Diabetic rats protected from macular oedema hallmarks with THR-687 treatment

, sits down with Michael Watson, Vice President of OraNet to discuss this year’s most pressing challenges in clinical research: From the overburdening of sites with studies delayed by COVID to difficulties with staff retention and how holistic site support and patient solutions can provide enough to relief to keep projects on time and within budget.

Mike Watson, Vice President of OraNet, unpacks some of the most pressing challenges to clinical research in today’s climate.

Tackling today’s top challenges of clinical research

Dr Daniel Choi and colleagues from the University of Pennsylvania, Philadelphia, investigated the effect of anti-vascular endothelial growth factor (VEGF) therapies in patients over the long term and overall found no association between the treatments and the risk of chronic kidney disease or end-stage renal disease.

They commented that while intravitreal anti-VEGF can reduce plasma-free-VEGF, the literature contains little information on the safety of long-term intravitreal anti-VEGF injections on the body and especially the kidney.

In this study, the investigators used a commercial and Medicare Advantage medical claims database to identify patients who had been treated with an intravitreal anti-VEGF agent and the numbers of injections administered over 4 years after the initial injection. The patients who met the inclusion criteria were divided into quartiles based on the number of injections they received, and the highest and lowest quartiles were compared.

The authors also looked at individual diseases, i.e., neovascular age-related macular degeneration (AMD), macular oedema associated with retinal vein occlusion (RVO), and diabetic retinopathy (DR). They also used Cox proportional regression analysis to assess an every-5-injection increase in the hazard of developing kidney disease, they described.

The results showed that 13,895 patients had received 1 to 3 anti-VEGF injections (lowest quartile) and 13,881 had received more than 21 or more injections (highest quartile).

In the lowest and highest quartiles, respectively, the patients with neovascular AMD received 6,228 injections (1 to 4 injections) and 6,172 had 24 or more injections (24 or more injections); those with macular oedema due to RVO, 573 (1 to 2 injections) and 580 (12 or more injections); and those with DR, 523 (1 to 2 injections) and 517 (13 or more injections).

The authors reported that for patients in the highest quartile, the weighted analysis showed no association overall with development of kidney disease (odds ratio [OR], 1.00, 95% confidence interval [CI], 0.98-1.01, 

 = 0.58) or in patients with neovascular AMD (OR, 0.99, 95% CI, 0.97-1.02, 

 = 0.48), decreased odds in macular oedema due to RVO (OR, 0.93, 95% CI, 0.86-0.99, 

 = 0.04), and increased odds in DR (OR, 1.12, 95% CI, 1.03-1.22, 

= 0.01). Cox analysis showed no association overall or for any subgroup (hazard ratio, 0.97-1.01, 

The authors concluded, “While logistic regression showed some association of the increased number of injections with kidney disease, the Cox analysis did not confirm these findings, suggesting time was a confounder in the logistic regression analysis.”

The study found no association between treatment and the risk of chronic kidney disease or end-stage renal disease.

Investigators examine long-term effects of anti-VEGF injection on renal function

A team of investigators has examined the relationship between dry eye and high myopia in Japanese teenagers and found what appears to be a reciprocal relationship between the disorders, according to a poster presented by Dr Osama Ibrahim Hirayama at the Association for Research in Vision and Ophthalmology’s 2022 annual meeting in Denver, Colorado, United States.

Dr Hirayama and colleagues from the Department of Ophthalmology at Keio University School of Medicine in Tokyo, conducted a retrospective, descriptive, consecutive case series to compare the dry eye conditions in 106 patients (age range, 10-19 years) with high myopia (mean age, 16.4 ± 2.2 years), 494 patients with mild myopia (mean age, 15.0 ± 2.6 years), and 82 subjects with no myopia (mean age, 13.8 ± 2.6 years).

All participants were assessed for myopia, astigmatic error, anisometropia., intraocular pressure, tear film break-up time, and fluorescein staining. A questionnaire was administered to record the dry eye-related symptoms of dryness, irritation, pain, fatigue, blurring, and photophobia.

The results showed that anisometropia and astigmatic error were significantly (

 < 0.001) greater among the patients with high myopia compared with the other groups. Compared with the subjects with no myopia, those with high myopia reported significantly more dryness (

Except for fatigue, most symptoms were associated with the myopic error, that is, dryness (β = -0.127, 

 = 0.034). The astigmatic error (β = -0.231, 

 < 0.001), short tear break-up time (β = -0.086, 

 = 0.028), and presence of diagnosed dry eye disease (β = -0.112, 

 = 0.003) were correlated with the myopic error.

“The current study demonstrated the significant clinical findings dry eye disease in patients with high myopia and indicated that dry eye disease might be associated with high myopia in teenagers,” investigators concluded.

In a poster presented at the Association for Research in Vision and Ophthalmology’s 2022 annual meeting, Dr Osama Ibrahim Hirayama and colleagues offered results that demonstrating that anisometropia and astigmatic error were greater among the patients with high myopia compared with the other groups. Compared with the subjects with no myopia, those with high myopia reported significantly more dryness, less photophobia, and less pain.

Relationship between dry eye disease and high myopia in teenagers investigated in study

At ARVO 2022, Dr Steven Yeh reviews the results of the Phase 3 PEACHTREE and AZALEA integrated study, revealing significant BCVA gains and low adverse event incidence in the Xipere (triamcinolone acetonide injectable suspension, Bausch + Lomb) arm.

Dr Yeh is a professor of ophthalmology and the Director of Retinal Disease and Uveitis at the Stanley M. Truhlsen Eye Institute at the University of Nebraska Medical Centre.

This integrated analysis looked at patients who received macular oedema for noninfectious uveitis. In PEACHTREE specifically, we treated patients with macular oedema due to noninfectious uveitis. And the AZALEA study looks specifically at safety in this cohort of patients.

And in this study, we looked at the efficacy signals as well as the safety signals, integrating these two cohorts of patients. What we found is that patients who received Xipere showed a significant best corrected visual acuity gain of up to two to three lines of visual acuity improvement at the week 24 time point when we combined the clinical trial data.

This is also reflected in reduction of macular oedema, specifically found that patients who received Xipere showed approximately 150 micron reduction in central subfield thickness, and this was sustained for the duration of the trial.

The other aspect that's very important related to this new technique for the treatment of posterior segment conditions is safety. What we found is that intraocular pressure rates were very favourable. In the Xipere arm specifically, about one in eight individuals showed elevation of intraocular pressure, compared to the slightly higher one and seven of individuals in the patients who were in the sham control arm.

When we broke this down further to the patients in the sham arm who received rescue therapy, we found that 25% of individuals who receive local intravitreal therapies showed an elevation of intraocular pressure, which is really compelling when we think about Xipere as a therapy that's nuanced, and a new technique for the treatment of macular oedema due to noninfectious uveitis.

Other adverse events were very well tolerated, and we're very excited about both the efficacy outcomes, as well as the safety variables as well. Again, visual acuity is very important to all of our patients and again, is related to the quality of life and what patients care about most. This is a new drug delivery technique that we're really looking forward to not only for uveitis, but other posterior segment conditions in the future.

Note: This transcript has been lightly edited for clarity.

The Phase 3 integrated PEACHTREE and AZALEA study data revealed strong safety and efficacy for triamcinolone acetonide via suprachoirodal injection.

Integrated study: Phase 3 PEACHTREE, AZALEA indicate significant BCVA gains, CST reduction

Ora's Caitlin Black, senior director and therapeutic area head of medical devices, discusses exciting new presbyopia IOL technology coming down the pipeline.

Hi, my name is Caitlin Black, senior director and therapeutic area head of medical devices at Ora. We are a full-service clinical development organization overseeing both drug and device clinical trials.

Just returning from ASCRS, I am most excited about the innovation in presbyopia. Presbyopia is the so-called "final frontier" in refractive surgery, and there are many advancements that are providing additional options to presbyopic patients.

We know that worldwide, 1.7 billion people are affected with presbyopia and they currently have limited options. Their quality of life is diminished due to the decreased visual acuity, and many are looking to be free of glasses or obtain spectacle independence.

Since 1949, when IOLs first for implanted we've seen many advancements in IOL technology, including multifocal accommodating IOLs, pinhole IOLs, and extended depth of focus IOLs. Now we're really focused on patient-reported outcomes in our medical trials.

At Ora we work very closely with our sponsors to design study protocols that take into consideration patient's quality of life. We do this through integrating quality of life questionnaires, supplements and being mindful of patient objectives when they enter a clinical trial for a premium IOL.

At Ora we partner with many sites, we have 800 sites that we partner with worldwide and we have individuals on the ground working in 25 countries. This allows us to have really high-quality oversight and monitoring of the clinical trials, which ultimately proceeds with high quality outcomes.

We know that there are many exciting advancements coming in presbyopic IOLs, many IOLs that are currently available outside of the US are entering clinical trial in the United States. I think the next challenge as more lenses become available will be to properly select the technology for the patient for individualized patient outcomes.

Ora's Caitlin Black, senior director and therapeutic area head of medical devices, talks about the next generation of ophthalmic device therapies and diagnostics, clinical trial updates and new innovations that are most exciting for presbyopia treatment.

Advancing IOL technology for treatment of presbyopia

 covered the evolution of gene therapy techniques in ophthalmology, use of polarisation-sensitive optical coherence tomography (PS-OCT) to recognize corneal abnormalities, an upcoming pharmaceutical for the treatment of cataracts and the announcement of a partnership between BRIM Biotechnology and Ora Inc. for the late-stage clinical development of lead drug candidate BRM421 for dry eye syndrome (DES).

Making strides in ophthalmology with modern gene therapy techniques

The are several available approaches in gene therapy. We can replace a disease-causing gene with a healthy gene or deactivate a gene that is not functioning properly. In addition, a modified or completely new custom-designed gene can be introduced to treat a disease.

The basic principle is to target missing or faulty genes in monogenic diseases. Usually the “gene therapy drug” is given only once; it carries an instruction to change the sequence of one or more proteins. This change is necessary if those essential proteins are produced in a faulty manner: either they are not produced in sufficient quantities or the catalysis process controlled by the protein is not working correctly.

Major pathobiochemical or pathophysiological pathways have been investigated intensively. Gene therapy products include plasmid DNA and viral or bacterial vectors: in a subset of diseases, cells are extracted, genetically modified and then re-introduced into the body but more commonly a viral vector is used, which entails eliminating the virus gene and using its ability to penetrate the cell to safely deliver the new information.

From an immunological perspective, the eye is the ideal target for gene therapy, which thus makes it likely that, in the future, highly successful gene therapy approaches will lead to cures for certain diseases of the eye.

The missing link in the recognition of corneal abnormalities

Polarisation-sensitive optical coherence tomography (PS-OCT) is a functional extension of the conventional form of OCT and exploits the polarisation properties of light. According to Dr Ritika Mullick, a fellow in Cornea and Refractive Services at Narayana Nethralaya Hospital, Bangalore, India, this imaging modality can aid the early recognition of disease-related changes before they can be seen topographically.

Dr Mullick explained that the human eye is known to have polarisation-altering tissues; using an ultra-high-resolution PS-OCT helps us to study the form birefringence caused by the underlying fibril structures in the corneal stroma. This, in turn, can enable users to detect subnormal distribution of collagen in corneal disorders.

In a clinic setting, this technology can demonstrate both normal corneal biomechanics and clear-cut cases of abnormalities, such as the development of post-SMILE ectasia.

Approaching pharmaceutical treatment for cataracts

A new treatment for cataract has shown extremely positive results in laboratory tests, giving hope that the condition, that currently can only be cured with surgery, could soon be treated with drugs.

A team of international scientists, led by Dr Barbara Pierscionek, deputy dean (Research and Innovation) in the Faculty of Health, Education, Medicine and Social Care at Anglia Ruskin University (ARU), have been carrying out advanced optical tests on an oxysterol compound that had been proposed as an anti-cataract drug.

According to a news release from ARU, in laboratory trials, treatment with the oxysterol compound VP1-001 showed an improvement in refractive index profiles – a key optical parameter that is needed to maintain high focusing capacity – in 61% of lenses. This means that the protein organization of the lens is being restored, resulting in the lens being better able to focus. This was supported by a reduction in lens opacity in 46% of cases.

“This study has shown the positive effects of a compound that had been proposed as an anti-cataract drug but never before tested on the optics of the lens,” Dr Pierscionek, who is also a member of the Medical Technology Research Centre at ARU, said in the release.

Dr Pierscionek added that it is the first research of this kind in the world.

“It has shown that there is a remarkable difference and improvement in optics between eyes with the same type of cataract that were treated with the compound compared to those that were not,” she said.

Strategic alliance combines resources to develop treatment option for dry eye syndrome

BRIM Biotechnology Inc. has entered into a new strategic partnership with Ora Inc. for the late-stage clinical development of lead drug candidate BRM421 for dry eye syndrome (DES).

According to a news release, BRIM intends to initiate Phase 3 clinical studies with Ora’s support later this year.

BRM421 is based on BRIM’s proprietary stem cell regenerative Pigment Epithelium-Derived Factor (PEDF) derived Short Peptide (PDSP) technology platform, which underpins several products in its pipeline and has the potential to be effective in multiple therapy areas and indications. The functional domain of PEDF chosen to generate PDSPs can be used to treat DES by speeding up the cornea repair process through stimulation of corneal stem cell proliferation and differentiation, anti-inflammation and meibomian gland recovery.

Dry Eye Syndrome is a chronic disease that affects the productivity and quality of life of 1.52 billion people worldwide.1 The COVID-19 pandemic has further exacerbated the problem, as prolonged time in front of screens is a risk factor for the disease.

Other risk factors include aging, eye surgeries, dry environments, long-term wearing of contact lenses, and autoimmune diseases. Unlike current treatments, BRM421 is a novel, first-in-class regenerative peptide therapy which, if successful, could offer patients full relief of symptoms plus repair the damage to the cornea.

An end-of-week review of what happened in ophthalmology from 14 May to 20 May.