QLS-111 is the second generation of the company’s initial formulation, QLS-101.

Qlaris Bio has released QLS-111, a second generation of its episcleral venous pressure (EVP) eyedrop, and Thurein Htoo, MS, MBA, the company’s CEO and co-founder, provided an update during the New Horizons Forum at the Glaucoma 360 conference at the Westin St. Francis San Francisco on Union Square.

Numerous therapies are available to treat primary open-angle glaucoma (POAG) and ocular hypertension (OHT) by addressing intraocular pressure (IOP), uveoscleral outflow, and conventional outflow facility. However, another target remains unaddressed, Htoo pointed out. 

“No treatment selectively targets EVP directly, and it the largest component of the IOP,” he said.

QLS-111 is the second generation of the company’s initial formulation, QLS-101. The first foray into the glaucoma arena with QLS-101 rapidly went into first-in-human studies and demonstrated excellent safety and tolerability profiles and efficacy, which supported the potential utility of the ATP-sensitive potassium channel modulator platform as a complementary mechanism that selectively targets the EVP.

High and low doses of QLS-111 were evaluated in a single-center clinical study to determine safety, tolerability, and efficacy in 21 healthy normotensive volunteers over the course of 14 days.

“In patients who received low-dose QLS-111, we observed a greater than 20% mean diurnal IOP reduction from baseline, with a mean reduction of -3.5 mm Hg from the baseline IOP of 16.7 mm Hg.” This result reached significance (p = 0.003) compared with the vehicle control,” Htoo explained.

The low dose was well tolerated with no stinging or burning upon instillation and no other ocular adverse events. Importantly, no clinically significant hyperemia was observed.

Because of the demonstrated IOP-lowering success targeting the EVP and the safety profile for treating POAG, there also may be a substantial benefit as an IOP-lowering agent for patients in whom the EVP has limited maximal pharmacotherapy, including in normal tension glaucoma that disproportionately affects Asian patients and for whom no therapies are approved on-label and for patients receiving minimally invasive glaucoma surgery devices that shunt flow into the distal outflow and episcleral venous systems, Htoo pointed out.

Finally, the drug may help patients with Sturge-Weber Syndrome.

“Having demonstrated meaningful IOP lowering in normo-tensive subjects, QLS-111 presents a substantive opportunity to be the first approved IOP-lowering agent for patients with normal tension glaucoma. With its novel mechanism, it may also serve to be an ideal complementary therapy in other forms of glaucoma,” Htoo concluded.

Articles

Thurein Htoo, MS, MBA, CEO and co-founder of Qlaris Bio, took the podium at the New Horizons Forum at the Glaucoma 360 conference in San Francisco to discuss the performance of the company’s episcleral venous pressure eyedrop, QLS-111. 

Glaucoma 360: Eyedrop targets and reduces episcleral venous pressure in glaucoma

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly, with 288 million individuals predicted to be affected by 2040,

 which creates a significant societal cost burden. With the increase in life expectancy, this burden will become greater, and arguably unsustainable, in the foreseeable future.

There is no cure or effective treatment currently approved for the non-neovascular form of AMD, although a multitude of therapeutic approaches are being investigated, which are reviewed in this article.

Antioxidant therapies/nutritional supplementation

Age-related eye disease study (AREDS) supplements

AREDS (NCT00000145 and NCT00594672), which was the largest multicentre trial for dry AMD, investigated the effects of antioxidant supplementation in affected individuals (n = 3640). A daily dose of vitamin E, vitamin C, beta-carotene, zinc oxide and cupric acid reduced the odds of developing advanced AMD in more than one-third of subjects with high-risk characteristics.

Subsequently, AREDS2 (NCT00345176) explored a new formulation composed of lutein, zeaxanthin and omega-3 polyunsaturated fatty acids in 4203 affected individuals, revealing no further significant reduction in the risk of developing advanced AMD.

The antioxidant eyedrop OT-551 (Othera Pharmaceuticals) was explored in a phase 2 trial (NCT00306488) after it demonstrated successful protection against retinal pigment epithelium (RPE) degeneration in preclinical models. Eleven individuals with bilateral geographic atrophy (GA) received topical 0.45% OT-551. Although the drug was deemed to be safe, no statistically significant differences in structural or functional outcomes were found between study and control eyes.

This protein has been identified as a component of drusen while also being an activator of the complement cascade. In a phase 2 study (NCT01342926), 191 individuals with GA received an intravenous anti-amyloid β monoclonal antibody (GSK933776, GlaxoSmithKline). The drug was well tolerated, but no clinical evidence of visual function improvement or decrease in the rate of GA enlargement was noted.

Another drug used to prevent the formation of oligomeric β-amyloid species, GAL-101 (Galimedix Therapeutics), has demonstrated neuroprotective effects in murine models of AMD. After positive results in a phase 1 trial (NCT01714960) in individuals with glaucoma, a phase 2 trial for both dry AMD and glaucoma is being developed.

The multicentre SEATTLE study (NCT01802866; n = 508) explored the effectiveness of oral administration of emixustat hydrochloride (ACU-4429, Kubota Pharmaceutical) in reducing the rate of progression of GA in individuals with dry AMD. The primary outcome was the mean annual growth rate of the GA area. The drug was found to be safe, with the most common adverse event (AE) being delayed dark adaptation, but it did not reduce the growth rate of GA.

Fenretinide acts by reducing retinol delivery through antagonism of serum retinol-binding protein. A phase 2 study (NCT00429936; n = 246) investigated the efficacy, defined by reduction in the growth of GA, of oral fenretinide in dry AMD. Significantly delayed dark adaptation was among the reported AEs, but the drug was deemed safe.

There was reduction in GA growth rate in treated individuals and a decrease in neovascularisation, which was not statistically significant compared with the placebo group due to the limited number of patients achieving the retinol-binding protein reduction criteria.

ALK-001 (Alkeus Pharmaceuticals) is a deuterated vitamin A, with a deuterium isotope replacement at carbon 20. After a repeat dose phase 1 study (NCT02230228) in 40 healthy volunteers found it to be safe, a placebo-controlled phase 3 trial started. The SAGA study (NCT03845582) is exploring the safety and efficacy of oral supplementation of ALK-001 in 300 individuals with GA secondary to AMD, with preliminary results expected soon.

Complement inhibitors and anti-inflammatory agents

Eculizumab (Soliris, Alexion) is a monoclonal antibody that acts by targeting the C5 complement protein. A phase 2 trial (COMPLETE; NCT00935883) explored the safety and efficacy of intravenous eculizumab in reducing the rate of GA area growth and drusen volume in AMD. Thirty individuals were randomised to the low- or high-dose or placebo cohort.

The drug was well tolerated, and none of the eyes converted to neovascular AMD during a total follow-up of 52 weeks. There was no significant change in drusen volume or in the GA growth rate.

Tedisolumab (LFG316) is an inhibitor of the complement protein C5. Its tolerability was explored in a phase 2 study using a single intravitreal injection (NCT01527500). Although the drug was deemed safe, commercial updates after 1 year of follow-up revealed no significant difference in GA area between the treated and the placebo groups.

Avacincaptad pegol (Zimura, Iveric Bio Inc.) is an anti-C5 aptamer to reduce the formation of the membrane attack complex. The GATHER1 study (NCT02686658) was a phase 2/3 trial that evaluated the safety and efficacy of avacincaptad pegol delivered intravitreally in subjects with GA. The trial consisted of two parts: 286 participants were randomised 1:1:1 to either 1 mg, 2 mg or sham in the first part, or 1:2:2 to 2 mg, 4 mg or sham in the second part.

The 12-month results revealed a statistically significant reduction of 27.4% (

 = 0.0072) in mean rate of GA growth (square root transformation) for the cohort receiving 2 mg, and 27.8% (

 = 0.0051) for the cohort receiving 4 mg, compared with the corresponding sham cohorts; hence, the primary efficacy endpoint was reached. The most frequent AEs were related to the injection procedure.

A second clinical trial (GATHER2; n = 448) is underway to confirm the efficacy of the drug in slowing the mean rate of GA growth (slope) area. The subjects were randomised to receive either monthly administration of 2 mg or sham during the first 12 months of the trial.

The most recent commercial reports, in September 2022, revealed no serious AEs. The incidence of choroidal neovascularisation (CNV) through month 12 was 6.7% in the treated group and 4.1% in the control group. In keeping with GATHER1, there was a statistically significant reduction in mean rate of GA growth (square root transformation) of 0.336 in the treated group vs 0.392 in the sham group (

Lampalizumab (Roche) is an antigen-binding fragment that targets and inhibits complement factor D. Two phase 3 trials with identical designs, CHROMA (n = 906; NCT02247479) and SPECTRI (n = 975; NCT02247531), explored intravitreal administration of lampalizumab in individuals with GA.

The drug was deemed safe, but efficacy was limited as it did not reduce GA enlargement compared with sham.

 A phase 3 open-label extension of these studies (OMASPECT; NCT02745119) was terminated in 2019 because of lack of efficacy.

Sirolimus (rapamycin, Pfizer) is an immunosuppressive agent used in the prevention of organ rejection. A phase 1/2 study (SIRGA; NCT00766649) evaluated subconjunctival administration of sirolimus in 11 individuals with GA. The drug was administered in a randomly assigned eye every 3 months for a total of 24 months.

The drug was well tolerated, although no signs of efficacy were identified. Furthermore, there was a decrease in mean best corrected visual acuity (BCVA) of 21 ETDRS letters, compared with 3 letters in the fellow eyes.

Pegcetacoplan (APL-2, Apellis) binds and inhibits the complement factor C3. A phase 2 study (FILLY; NCT02503332) explored the safety and efficacy of pegcetacoplan in individuals with GA. Subjects were randomised in a 2:2:1:1 ratio to receive 15 mg of pegcetacoplan intravitreally either monthly, every other month (EOM), or sham (monthly or EOM).

Patients in the treated groups showed reductions in GA growth rate of 29% and 20%, respectively, which were significant compared with the sham group, although there was no significant difference in BCVA outcomes. AEs included endophthalmitis in three subjects and an increase in exudation of 20.9% in the monthly and 8.9% in the EOM arm.

The related phase 3 studies DERBY and OAKS (NCT03525600 and NCT03525613) are ongoing. Reports from the sponsors reveal reduction in GA lesion growth from baseline of 19% (

 = 0.003) in the EOM group in the DERBY study, and 22% (

 = 0.0002) in the EOM group in the OAKS study, compared with sham across 24 months.

A multicentre phase 2a study (NCT03626636) explored the safety and efficacy of 1 mg risuteganib (Luminate, Allegro), a drug that acts by binding and inhibiting types of integrin heterodimers, in subjects with dry AMD. Thirty-nine subjects completed the study and were enrolled in either the treatment or control arm.

The primary endpoint, defined as the proportion of subjects with an eight or more ETDRS letter gain from baseline, was met by 48% of the risuteganib group at week 28 and 7% of the sham group at week 12.

 A trend toward improvement of colour vision and microperimetry parameters tested in the individuals treated with risuteganib was noted.

 No serious AEs were reported during a 32-week period.

The safety of a ciliary neurotrophic factor implant was explored in a human phase 1 trial in 10 individuals with retinitis pigmentosa (NCT00063765). The implant was safe, with AEs limited to anterior chamber activity that did not require further treatment and a procedure-related choroidal detachment

A phase 2 trial (NCT00447954) explored the same implant technology in individuals with dry AMD. There was no difference in GA area or functional improvement in BCVA between the treated and sham arms.

Evidence suggests that this alpha2-adrenergic receptor agonist may have neuroprotective properties.

 A sustained-release intravitreal implant, the brimonidine Drug Delivery System (Brimo DDS), was explored in a phase 2a study (NCT00658619). Individuals with GA (n = 113) were randomised to receive 132 µg, 264 µg or sham.

 ≤ 0.032) response in GA area growth of 1.78 mm

, respectively. Furthermore, AEs were mainly related to the procedure.

BEACON was a phase 2b study (NCT02087085) exploring the same implant in 310 individuals with GA. Patients were randomised to receive either 400 µg or sham, 3-monthly.

There was a significant decrease in GA growth in the treated arm, of 0.36 mm

 = 0.017) at months 24 and 30, respectively.

 AEs were mild and limited to the injection site. Two phase 3 studies exploring Brimo DDS at 200 µg and 400 µg (IMAGINE and ENVISION) are planned.

A phase 1 dose-escalation trial is exploring AAVCAGsCD59 (Janssen R&D, LLC) in individuals with dry AMD (NCT03144999). Seventeen eyes received intravitreal injections of AAVCAGsCD59 across three doses, with no dose-limiting events. Three individuals in the high-dose cohort experienced mild uveitis and vitritis that required 6–8 weeks of anti-inflammatory therapy, although the drug was deemed safe.

A phase 1/2 dose-escalation study (FOCUS; NCT03846193) explored subretinal delivery of GT005 (Gyroscope Therapeutics), which also acts by regulating the complement cascade. This is an adeno-associated viral vector encoding complement factor I, a down-regulator of the C3b breakdown cycle that regulates the alternative complement cascade.

The last update by the sponsors revealed a good safety profile.

Two other phase 2 trials administering subretinal GT005 were then started, EXPLORE (NCT04437368) and HORIZON (NCT04566445), both of which are currently recruiting.

A phase 1 study (NCT04246866) is investigating the safety of intravitreal GEM103 (Gemini Therapeutics), a human recombinant complement factor H protein, in 12 individuals with GA. The drug was well tolerated, with only four participants experiencing AEs, mainly relating to the injection procedure, with no inflammation observed. No CNV occurred, and visual acuity (VA) was stable throughout the 8-week follow-up period.

This led to the ongoing phase 2a study (ReGatta; NCT04643886) evaluating GEM103 in individuals with dry AMD, which was subsequently terminated by sponsors because there was no evidence of further benefit.

Subretinal administration of palucorcel (CNTO 2476, Janssen), a compound derived from human umbilical cord tissue, was investigated in a phase 1/2 study (n = 13; NCT01226628). The procedure involves the use of the iTrack Model 275 microcatheter for an ab externo approach. This procedure had a high rate of AEs, with 17.1% of subjects experiencing retinal detachments and 37.1% experiencing retinal perforations. When well tolerated, it was associated with improvements in VA, with 24.1% gaining ≥15 letters in BCVA.

The corresponding phase 2b study (PRELUDE; NCT02659098) used a novel subretinal delivery system with a suprachoroidal surgical approach to treat 21 subjects with GA. Most ocular AEs were mild and resolved within 1 month, but there was no demonstrated efficacy in GA area growth or VA.

The safety of subretinal RPE transplantation using human embryonic stem cell-derived RPE (MA09-hRPE, Astellas) was evaluated in nine individuals with advanced dry AMD in a phase 1/2 open-label study (NCT01344993). Six individuals showed a BCVA improvement of at least 11 ETDRS letters, whereas the other three maintained stable vision.

The procedure was considered to be safe. Interestingly, a significant number of individuals developed patches of increased subretinal pigmentation at the border of the atrophic areas.

Subretinal implantation of a human embryonic stem cell-derived RPE cell on an ultrathin parylene substrate (CPCB-RPE1, Regenerative Patch Technologies) was explored in a phase 1/2 study (n = 16; NCT02590692). Four subjects in the first cohort had serious AEs, such as retinal haemorrhage, focal retinal detachment or RPE detachment; this was mitigated in the second cohort due to improved haemostasis used during surgery, and the implant was deemed well tolerated.

Four subjects showed an increase in BCVA of at least 5 letters in the 12-month follow-up.

After reversal of mitochondrial dysfunction and deposit formation in preclinical models of sub-RPE deposits, elamipretide (Stealth BioTherapeutics), a cardiolipin-protective compound, was explored in human trials.

ReCLAIM (NCT02848313) was a phase 1 study investigating daily subcutaneous delivery of 40 mg elamipretide in individuals with intermediate AMD. At week 24, patients with non-central GA (n = 15) showed a mean increase in low-luminance VA of 5.4 ± 7.9 letters and BCVA of 4.6 ± 5.1 letters, whereas patients with high-risk drusen (n = 19) had mean increases of 3.6 ± 6.4 letters (

 = 0.006) in BCVA and low-luminance VA, respectively.

The related phase 2 trial, ReCLAIM-2(NCT03891875), did not achieve its primary endpoint. It did demonstrate enhanced ellipsoid zone preservation through reduction of progressive attenuation but did not achieve a significant change in GA area or low-luminance VA.

Laser intervention in early stages of AMD (LEAD) was a randomised placebo-controlled study (NCT01790802) exploring the safety and efficacy of subthreshold nanosecond laser in individuals with early high-risk AMD. There was no significant difference in the progression to late AMD in the treatment group compared with sham.

The follow-on study was in keeping with these findings and revealed no difference in rate of progression over a 60-month period. However, a post hoc analysis suggested that disease progression was significantly slower (

 = 0.007) in individuals without coexisting reticular pseudodrusen.

The management of AMD is currently limited to the detection and early treatment of CNV. Several clinical trials in different phases failed to meet outcomes despite promising preclinical evidence, although others have shown significant potential.Given the ever-growing burden that AMD represents globally, it is likely that further clinical trials will be developed—with optimism of new treatments approved in the future.

Dr Guimaraes is a clinical research
fellow at Moorfields Eye Hospital and PhD candidate at UCL Institute of Ophthalmology (both in London, UK) and previously was an ocular genetics fellow at Wills Eye Hospital in Philadelphia, Pennsylvania, USA.

Michel Michaelides, BSc, MB, BS, MD(Res), FRCOphth, FACS

Prof. Michaelides is a consultant ophthalmologist at Moorfields Eye Hospital in the departments of Medical Retina, Inherited Eye Disease and Paediatric Ophthalmology and a professor of ophthalmology at the UCL Institute of Ophthalmology in London, UK.

The authors have no conflicting relationships with the subject of this article.

Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. 

Cabral de Guimaraes TA, Daich Varela M, Georgiou M, Michaelides M. Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions. 

Sangiovanni JP, Agrón E, Meleth AD, et al. ω-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. 

Chew EY, Clemons TE, Sangiovanni JP, et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. 

The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. 

Wong WT, Kam W, Cunningham D, et al. Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial. 

Rosenfeld PJ, Berger B, Reichel E, et al. A randomized phase 2 study of an anti-amyloid β monoclonal antibody in geographic atrophy secondary to age-related macular degeneration. 

Rosenfeld PJ, Dugel PU, Holz FG, et al. Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration: a randomized clinical trial. 

Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. 

Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. 

Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. 

The most promising recent interventional trials for investigational therapies in dry age-related macular degeneration are highlighted by the authors.

Dry AMD: A review of ongoing, completed and future treatments

According to the companies, ML6710i is a transportable ophthalmic laser that is controlled from an iPad mobile application.

Bausch + Lomb Corp. and biomedical laser firm Modulight Oyj announced Wednesday the US Food and Drug Administration has approved their ML6710i photodynamic laser for use with the eye-health company's photodynamic therapy, Visudyne.

Visudyne (verteporfin for injection) photodynamic therapy (PDT) is for the treatment of patients with predominantly classic subfoveal choroidal neovascularisation, or the creation of abnormal choroidal blood vessels, due to age-related macular degeneration (AMD). ML6710i is expected to be available for eye care professionals during the first half of 2023.

In a news release, Christina Ackermann, president, Ophthalmic Pharmaceuticals, Bausch + Lomb, pointed out that PDT continues to be an important treatment option for eye care professionals who are looking to treat patients with predominantly classic subfoveal choroidal neovascularisation.

“The approval of ML6710i, eye care professionals now have a new state-of-the-art photodynamic laser that addresses a significant unmet need in PDT and is specifically designed to deliver VISUDYNE to patients who suffer from wet AMD with persistent fluid,” she said in the release.

According to the companies, ML6710i is a transportable ophthalmic laser that is controlled from an iPad mobile application. The laser’s beam shaping unit, which can be fit into all common slit lamps used for eye examinations, is formed into a circular, uniform spot to enable efficient treatment delivery of Visudyne.

“As a result of our efforts with Bausch + Lomb, along with the feedback that many eye care professionals provided to our teams, we are thrilled to bring forward an innovative cloud connected laser platform that the ophthalmology community can use to deliver VISUDYNE to patients in need of treatment of choroidal neovascularisation due to AMD,” Seppo Orsila, founder and CEO, Modulight, said in the release.

Visudyne is an injectable photosensitizer drug that is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to AMD, pathologic myopia or presumed ocular histoplasmosis. It is activated through use of a photodynamic laser via direct laser excitation, delivering a targeted approach that specifically destroys abnormal choroidal blood vessels to help prevent further disease progression and help patients maintain their vision.

According to a news release from Bausch + Lomb and biomedical laser company Modulight, the FDA has approved the ML6710i photodynamic laser for equivalent use with Visudyne.

US FDA approves to Ml6710i laser for use with Visudyne

An international team of researchers reported that atropine drops should be discouraged as a standard therapy after trabeculectomy because of the resultant greater and longer lasting reduction in visual quality.

 Dr Panagiotis Laspas, MD, from the Department of Ophthalmology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany, was the lead study author.

The investigators explained that atropine has cycloplegic and mydriatic properties, the latter of which that can cause multiple visual side effects,

 including disrupted accommodation, blurred vision, haloes, and light sensitivity. The potential systemic absorption of the drug can affect the cardiovascular system,

 causing dysrhythmias, and affect patients’ mental state, causing confusion, restlessness and emotional lability.

They conducted a prospective randomised study of 40 patients who underwent standard trabeculectomy with mitomycin C at the Department of Ophthalmology Department, University Medical Center of Mainz. Postoperatively, all patients received ofloxacin and dexamethasone eye drops. The patients then were randomised into 2 groups of 20 patients each; 1 group (the intervention group) also received atropine eye drops postoperatively and were instructed to instill the drops 3 times daily for 2 days to stabilise the anterior chamber. All patients completed a visual quality questionnaire preoperatively and 2 and 6 weeks postoperatively.

The results showed that visual quality decreased postoperatively in all patients.

The authors reported, “Patients who received atropine eye drops described a greater and longer-lasting reduction in visual quality than those who did not receive atropine eye drops. Trabeculectomy often leads to a transient reduction in visual quality. This reduction was greater in severity and duration in patients who received postoperative atropine eye drops.”

Based on the results, the investigators suggested that “unless there is an underlying medical necessity, we would discourage the application of atropine as a standard therapy for trabeculectomy surgery.”

Laspas P, Maier E, Schuster A, et al. Effects of postoperative atropine eye drops on visual quality in patients undergoing trabeculectomy. 

Joachimsen L, Farassat N, Bleul T, et al. Side effects of topical atropine 0.05% compared to 0.01% for myopia control in German school children: A pilot study.

Merli GJ, Weitz H, Martin JH,et al. Cardiac dysrhythmias associated with ophthalmic atropine.

Jimenez-Jimenez FJ, Alonso-Navarro H, Fernandez-Diaz A, et al. Neurotoxic effects induced by the topical administration of cycloplegics. A case report and review of the literature. 

Unless there is an underlying medical necessity, researchers discourage the application of atropine as a standard therapy for trabeculectomy surgery in a recent study.

Atropine instillation after glaucoma surgery may impair vision, prolong rehabilitation time

 found that the disparities in access to ophthalmologic care for paediatric patients have increased over the past 15 years and are associated with lower socioeconomic status, according to Hannah Walsh, BS, and colleagues. She is from the University of Miami Miller School of Medicine in Miami, Florida, USA.

The investigators underscored the importance of accurate, publicly available online databases to identify the nearest paediatric ophthalmologists.

They commented, “The geographic distribution of paediatric ophthalmological care has not been reported since 2007; understanding this distribution could shed light on potential avenues to increase access, which is a necessary first step in addressing the paediatric ophthalmological needs of underserved areas.”

Ms Walsh and associates conducted a cross-sectional study to analyse the geographic distribution of paediatric ophthalmologists relative to the US population demographic characteristics. They used public databases from the American Academy of Ophthalmology and American Association for Pediatric Ophthalmology and Strabismus to identify the locations of US paediatric ophthalmologists as of March 2022.

Locations and numbers of paediatric ophthalmologists

The analysis identified 1,056 paediatric ophthalmologists, most of whom were in the most highly populated states: California (11.0%), New York (9.2%), Florida (6.5%) and Texas (5.9%).

“A total of 2,828 of 3,142 counties (90.0%) and 4 of 50 states (8.0%) had no paediatric ophthalmologists. In 314 counties (10.0%) with 1 or more paediatric ophthalmologists, the mean number of paediatric ophthalmologists per million persons was 7.7 (range, 0.4-185.5),” the investigators reported.

Household income was a factor, in that the counties with 1 or more paediatric ophthalmologists had a higher median household income compared with counties with 0 paediatric ophthalmologists ($70,230.59 vs $53,263.62, respectively), a difference that reached significance (

Other factors identified were the proportions of families in each county without internet access (8.0% vs 4.7%, 

 < 0.001), patients younger than 19 years without health insurance (5.7% vs 4.1%, 

 < 0.001), and households without vehicle access (2.1% vs 1.8%) (

 = 0.001) in counties with no compared with counties with 1 or more paediatric ophthalmologists.

The authors emphasised that disparities in geographic access to paediatric ophthalmologists persisted in 2022, and the range of practitioner to million persons has increased since 2007. Disparities in practitioner distribution were associated with lower socioeconomic status. Accurate publicly available information on the locations of paediatric ophthalmologists is warranted to increase access to care.

Walsh HK, Parrish A, Lucko L, et al. Access to pediatric ophthalmological care by geographic distribution and US population demographic characteristics in 2022. 

 Published online January 26, 2023. doi:10.1001/jamaophthalmol.2022.6010

Accurate publicly available information on the locations of paediatric ophthalmologists is warranted to increase access to care.

Understanding disparities in availability of paediatric eye care: US report

Progress is being made in the treatment modalities for inherited retinal diseases. Specifically, the delivery of lipid nanoparticle (LNP)-based mRNA seems promising to treat these diseases, according to Marco Herrera-Barrera, MD, from the Department of Pharmaceutical Sciences, College of Pharmacy, Robertson Life Sciences Building, Oregon State University, Portland, USA.

Until now, LNP-mediated mRNA delivery could only be achieved to the retinal pigment epithelium (RPE) and Müller glia. “LNPs must overcome ocular barriers to transfect neuronal cells critical for visual phototransduction, the photoreceptors,” the investigators explained.

They hypothesised that chemically decorating LNPs with a short 7-nucleotide oligomer peptide would facilitate penetration into the neural retina. Previous studies have shown that by crossing biologic barriers, peptides enhanced drug delivery, imaging agents and nanoparticle drug targeting.

In this study, they used a peptide library to identify peptide sequences that bind the neural retina in vivo. Decoration of the peptides on the surface of LNPs with varying surface densities resulted in successful delivery of mRNA to the neural retina in a mouse model, they reported.

“These results translated to the more clinically relevant nonhuman primate, where robust protein expression was observed in the photoreceptors, Müller glia, and RPE. Overall, we identified peptide-conjugated LNPs that can facilitate the delivery of mRNA to the neural retina, expanding the utility of LNP-mRNA therapies for inherited blindness,” they concluded.

Herrera-Barrera M, Ryals RC, Gautam M, et al. Peptide-guided lipid nanoparticles deliver mRNA to the neural retina of rodents and nonhuman primates. 

Albertini B, Mathieu V, Iraci N, et al. Tumor targeting by peptide-decorated gold nanoparticles. 

Hennrich U, Kopka K. Lutathera: The first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. 

The delivery of lipid nanoparticle-based mRNA to the retina is encouraging, according to researchers.

Inherited retinal diseases: Progress being made with treatment modalities

Polish investigators led by Dr Michal Orski, PhD, Department of Ophthalmology, Ludwik Rydygier Memorial Specialized Hospital, Krakow, Poland, reported that fractionated robotic radiotherapy of the tumours applied near the optical pathway is safe and does not impact vision despite minor changes in the anatomy of the optic nerve.

Dr Orski and colleagues undertook a prospective observational study of patients who had been irradiated using the CyberKnife system (Multiplan 4.6 Accuray, Sunnyvale, California, USA) to treat benign tumours. 

Patients had a variety of pathologies that included 10 with cavernous sinus meningioma, 9 with pituitary adenoma, 5 with meningioma of the anterior and middle cranial fossa, 5 with meningioma in the region close to optic chiasm, 3 with craniopharyngioma, and 2 with orbital meningioma, the authors described.

All patients received 3 fractions in doses from 600 to 800 centigray. The investigators used the pre-treatment baseline as the control follow-up examinations after radiotherapy. They then assessed the impact of the radiation on the eye based on anatomic and functional changes.

The anatomic features that were evaluated where the ocular surface, central corneal thickness (CCT), endothelial cell density (ECD), lens densitometry, central macular thickness (CMT), and retinal nerve fiber layer (RNFL); the functional features evaluated were the best-corrected visual acuity (BCVA), intraocular pressure (IOP), visual field (VF), and visual-evoked potentials (VEP).

Patients underwent ophthalmologic examinations before radiotherapy and 6, 12, 18, and 24 months after radiotherapy.

“We did not observe any significant changes in BCVA, IOP, CCT, CMT, VF, VEP, and slit-lamp examination during the 2-year observation,” the authors reported.

They did see significant decreases in the ECD and RNFL at all of the evaluations. The decrease in the cell density did not impact the corneal function and vision; the decrease in the RNFL did not impair visual function, they pointed out.

The investigators concluded, “Fractionated robotic radiotherapy of the tumours close to the optical pathway is safe and does not impair patient’s vision. Minor changes found in optic nerve anatomy (RNFL thinning) might be related to the radiation effect or tumour compression. The causal relation between low doses of radiation delivered to the cornea and the observed significant but slight decrease in ECD is uncertain. The observed changes did not cause visual disturbances perceivable by the patients.”

Orski M, Tarnawski R, Wylegala E, Tarnawski D. The impact of robotic fractionated radiotherapy for benign tumors of parasellar region on the eye structure and function. 

The investigators set out to study if treatment of the tumours close to the optical pathway is safe and whether it may impair a patient’s vision.

Exploring robotic fractionated radiotherapy for benign ocular tumours

A common neurodegenerative disorder, Alzheimer disease (AD) is typically diagnosed symptomatically because of the high cost and invasiveness of alternative methods like positron emission tomography scans and lumbar punctures. With the identification of microvascular and neurosensory structural alterations in the retinas of individuals with AD, non-invasive retinal imaging may be an adjunctive or even an alternative means of detecting AD early.

To test this possibility, the Eye Multimodal Imaging in Neurodegenerative Disease (iMIND) lab at Duke University applied modern machine learning techniques to retinal images and clinical patient data, as shared in their recent publication in the 

 The model was able to distinguish those with symptomatic AD from cognitively normal controls, serving as a proof of concept for using the retina as a “window to the brain” and exhibiting promise for artificial intelligence (AI) as a powerful tool in the diagnosis of AD.

For this study, the iMIND team collected and used the following types of retinal images: ganglion cell-inner plexiform layer (GC-IPL) thickness colour maps from optical coherence tomography (OCT), superficial capillary plexus en face 3 × 3 mm and 6 × 6 mm OCT angiography (OCTA) images centred on the fovea, ultra-widefield (UWF) scanning laser ophthalmoscopy (SLO) colour fundus photos, and UWF SLO fundus autofluorescence images.

In addition to the raw images, subjects’ age, sex and visual acuity as well as quantitative metrics of retinal microvasculature and structure from the OCT and OCTA scans were included.

The ground truth (AD or cognitively normal) was determined by a team of expert neurologists; participants with underlying conditions, which could bias the detection accuracy, were excluded from the study.

The images were manually assessed for quality prior to adding to the input dataset. Poor-quality images were excluded and the UWF images were cropped to a standardised region of interest to avoid or remove artifacts, yielding high-fidelity data.

When imaging data are the primary input for a machine learning model, one of the most powerful and commonly used subtypes of machine learning is a convolutional neural network (CNN), which employs hierarchical learning to assimilate the complexities of images and spatially inconsistent features.

CNNs decompose image inputs into more basic visual features such as lines and edges, which can themselves combine to form shapes that in turn can combine to form groups of shapes. Each of these steps is referred to as a “layer” of the CNN.

By simplifying a complex problem into several simple problems, the model can efficiently learn the proper way to extract the useful features and biomarkers from images.

With a dataset of 222 eyes from cognitively normal patients and 62 eyes from AD patients, the team divided the data into training, validation and testing sets for the model.

The training set included 34 AD and 152 cognitively normal eyes (18.3% AD) whereas the validation set included 6 AD and 24 cognitively normal eyes (20.0% AD).

The test set included 22 AD and 46 cognitively normal eyes (32.3% AD) that were accrued a year after the training and validation images by different imagers using the same imaging machines. A model should be capable of accurate predictions using images collected by photographers different from those who supplied its training dataset.

The model was initially trained on the training set and had its parameters adjusted by feedback from the area under the receiver operating characteristic (AUC) and accuracy metrics when tested against the validation set.

After adjustments were finalised, the model was trained on both the training and validation data and tested against the test set (data not seen during any part of the training or parameter adjustment process). Eleven models differing in their combinations of inputs were trained and tested, and their scores reported with the AUC metric.

The model using GC-IPL maps, quantitative OCT and OCTA data, and patient data achieved the best-performing peak average AUCs of 0.861 (95% confidence interval [CI] 0.727, 0.995) on the validation set and 0.841 (95% CI 0.739, 0.943) on the test set.

This performance was impressive, especially when considering it had been trained on a small dataset. Increasing the size of the dataset could yield even better performance for predicting AD using retinal images and related metrics.

The CNN model made significantly accurate predictions for the presence of symptomatic AD via retinal imaging and clinical data, providing an excellent proof of concept. The project illuminated the capabilities of using the retina to detect AD, showing promise for AI detection that, if developed, could serve as a non-invasive means of screening and expand patient access to care.

Although the data were curated meticulously and filtered for quality and ocular artifacts, the dataset was relatively small and did not assess racial diversity.

The AD model was limited to data collected from AD patients enrolled from the Duke Memory Disorders Clinic and cognitively normal participants from the Duke Alzheimer Disease Research Center or community volunteers aged 50 years or older. As a result, 284 eyes were used: 222 from cognitively normal participants and 62 from participants with symptomatic AD.

Having significantly more distinct data points would further improve the designed model’s ability to generalise and make more accurate predictions. Understandably, the high-quality dataset was small but leaves room for improvement in future models. The struggle of any machine learning venture is robust data, and image and data inputs from diverse populations will need to be incorporated in future AD detection efforts.

The iMIND team took several measures to ensure that a primary challenge in machine learning, overfitting, was avoided.

Overfitting is when a model learns to associate ungeneralisable details with the output. More specifically, when the model associates a participant’s images, quantitative and patient data with the output rather than learning what features of the inputs across the entire dataset accurately contribute to the output.

Instead of creating a CNN feature extractor for each imaging modality, a modified, parsed ResNet18 was used, reducing the trainable weights to one-third of what they could have been. The team’s model was especially prone to overfitting because of the small dataset, which could cause the model to memorise the images associated with a certain output as opposed to learning the features of the inputs predictive of the output (AD or not AD).

Having fewer parameters reduces the possibility of overfitting when paired with techniques such as regularisation (penalises the learning of complex, noisy features), which the team employed. More data would enable the exploration of a larger model to assess whether a slight increase in complexity would improve overall accuracy in detecting AD without the issue of rapid overfitting on small datasets.

Future steps for this CNN model would be to acquire a larger, more diverse population to ensure a greater density of sample points for the model to learn from, improving the model’s generalisability. Increasing the dataset with more high-quality images would yield the highest return on prediction accuracy and would additionally offer the ability to assess the benefits of an augmented model size.

Future efforts should focus on AD detection in patients with underlying conditions that also impact retinal imaging, such as diabetes and glaucoma, as well as using different imaging formats because image standardisation is still evolving across imaging platforms in ophthalmology.

Notably, the automation of quality assessment procedures is a crucial task to facilitating future endeavours, as manually determining the quality of images and filtering for high-quality images are time- and resource-intensive tasks.

Duke University’s interdisciplinary team at iMIND lab established the potential of machine learning to detect symptomatic AD and the ability to use retinal imaging paired with numerical and categorical data for the task. The effort yielded an important proof-of-concept model, expounding promise for AI application in this exciting field.

David Bearden; Terry Lee, MD; Alex Richardson; C. Ellis Wisely, MD, MBA; Ricardo Henao, PhD; Dilraj S. Grewal, MD, FASRS; Sharon Fekrat, MD, FASRS

The authors are part of the interdisciplinary iMIND AI team, which investigates the use of multimodal retinal and choroidal imaging to identify neurodegenerative disease using AI at Duke University, Durham, North Carolina, US. No author has any financial declaration relevant to the article.

Heringa SM, Bouvy WH, Van Den Berg E, et al. Associations between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities: A systematic review.

Wisely CE, Wang D, Henao R, et al. Convolutional neural network to identify symptomatic Alzheimer’s disease using multimodal retinal imaging. 

An interdisciplinary team at Duke University has developed a proof-of-concept machine learning model capable of detecting symptomatic Alzheimer disease using multimodal retinal imaging data.

Retinal imaging to detect Alzheimer disease: machine learning model

Dementia is a progressive deterioration in cognitive function not related to normal ageing and secondary to different diseases. It results from various diseases and injuries affecting the brain. The most commonly affected areas include memory, visuospatial function, perception, orientation, language, attention and problem solving.

The progression of the manifestations is usually slowly deteriorating, but it changes depending on the different types of dementia. The manifestations include behavioural and psychological symptoms. Behavioural symptoms include agitation, restlessness, inappropriate conduct, sexual disinhibition and aggressiveness. Psychological symptoms include depression, hallucinations and delusions, apathy and anxiety.

 There is no cure for dementia, even with nonpharmacologic and pharmacologic management. Nonpharmacologic management includes physical activities, social stimulation, intellectual activities, exercise and socialisation. Pharmacologic treatment may offer limited improvement in Alzheimer and Parkinson disease.

The procedure facilitates an independent life, better care and fewer costs.

Retinal imaging to detect Alzheimer disease: machine learning model

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