Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

Cheryl Guttman Krader, BS, Pharm

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Range of unanswered questions may be addressed by ongoing research

This article was reviewed by Donald Tran, MD


	
	An abundance of evidence from randomised, controlled clinical trials supports the use of topical atropine to prevent myopia progression.

Study results also show that using a low dose of atropine minimises adverse effects and myopic rebound after treatment discontinuation. In addition, the findings indicate that the pharmaceutical formulation affects efficacy, said Donald Tan, MD.

Now, research in this area is continuing and is investigating not only the use of atropine for preventing myopia progression, but also whether it can prevent or delay the onset of myopia.
	
	

 Low-dose atropine for myopia in children: two years of experience 

Dr Tan is adjunct professor in ophthalmology, Duke - National University of Singapore Medical School, and Visiting Senior Consultant, Singapore National Eye Centre, Singapore. He previously served as Director of the Singapore Eye Research Institute (SERI) and the Singapore National Eye Centre. 

Over a period of two decades, the SERI completed five randomised controlled trials on myopia progression involving approximately 1,900 children, including two studies investigating atropine [ATOM1 (Atropine for the Treatment of Myopia) and ATOM2].
	
	Now, SERI is conducting ATOM3 that is testing atropine as intervention to prevent or delay myopia onset in children.

Discussing atropine treatment as a pharmaceutical strategy for myopia control to address the global myopia burden, Dr Tan said, “A Cochrane systematic review published in 2011 identified over 180 published interventional studies for approaches to reduce myopia progression.
	
	Since then, more than 30 clinical trials on the use of atropine eye drops for myopia control were registered on the 

“These studies tested or are testing atropine in concentrations ranging from 1% to 0.005% in eyedrop, gel and ointment formulations and as standalone treatment or with adjunctive therapies that include orthokeratology, soft bifocal contact lenses, ketorolac, acemanisodiamine and acupuncture. Clearly, this is a fervent area of interest.”

7 pediatric eye myths parents should stop believing 


	Studies investigating topical atropine began in Asia in the 1970s. Despite the long-term history of use and evidence of its efficacy, the mechanism of action by which atropine may control myopia is unknown, Dr Tan said. 

“Initially it was thought that atropine might block accommodation, but that is now known not to be true. The current concept is that it works either through a neurochemical cascade that begins with muscarinic receptors at the retina or via a non-muscarinic mechanism involving a direct effect on scleral fibroblasts mediated by inhibition of glycosoaminoglycan synthesis,” he said.
	
	

Dr Tan is chair of the previous ATOM studies. ATOM1 was a 2-year interventional trial launched in 1999 that compared atropine 1% with placebo in children ages 6 to 12 years old with –1 to –6 D myopia.
	
	The results showed that atropine significantly reduced myopia progression and its effect on refraction strongly correlated with a reduction in increase of axial length.
	
	However, the treatment was associated with significant side effects, and 1 year after it was stopped, significant rebound of both axial length and spherical equivalent were observed.

To try to minimise treatment-related side effects, ATOM2 tested lower doses of atropine: 0.5%, 0.1% and 0.01%. It enrolled children aged 6–12 years with ≥–2 D of myopia.
	
	

Exploring laser vision correction for myopia with/without astigmatism 


	
	The trial had a 1-year washout period following 2 years of treatment, and atropine 0.01% was restarted for 2 years in any child whose myopia rebounded during the washout. 

Results from ATOM2 demonstrated that both atropine-related ocular adverse events and myopic rebound decreased with decreasing dose.
	
	The study also found that restarting atropine treatment the 0.01% formulation was able to reverse myopia progression that occurred during the washout year. 

“At the end of 5 years, treatment with atropine 0.01% was associated with a 50% reduction in myopia progression,” Dr Tan said. 

Myopia may prove beneficial in preventing DR development


	Based on epidemiological evidence that a younger age of onset is associated with higher degrees of myopia measured both by higher SE and longer axial lengths, ATOM3 is designed to test whether intervention with atropine can prevent or delay the onset of myopia. 

“We are doing this study in Singapore where we can confidently predict that 5-year-old children whose refraction is between +1 and –0.49 D will become myopic later in life. We call these children pre-myopes,” said Dr Tan. 

ATOM3 is enrolling children aged 5–9 years whose refractive error (by cycloplegic refraction) is between +1 and –0.49 D) and who have at least one parent with myopia. They are being randomised to receive 0.01% atropine or placebo. Treatment will be continued for 2.5 years and then children will be followed during a 1-year washout period. 
	
	

PEDIG focusing on binocular activities for amblyopia 

Synthesising the contemporary literature 


	A network meta-analysis of randomised controlled studies investigating interventions for myopia control in children published in 2016 by Huang et al. found that moderate and high dose atropine markedly slowed myopia progression.
	
	In 2017, Gong et al. published a meta-analysis that included 19 studies of atropine involving more than 3100 children. 

The investigators concluded that the data showed the efficacy of atropine was dose-independent within the dose range studied, whereas the adverse effects were dose dependent, increasing with increasing dose. 

Dr Tan said that the authors stated that low-dose atropine seems to herald a new therapeutic scenario that decreases the adverse effects and seems to decrease the rebound effects.
	
	

Questionaire assesses vision in pediatric eye cases 

“They even went on to suggest that pharmaceutical companies could produce 0.01% atropine commercially to aid further global research.”

In 2017, the American Academy of Ophthalmology Technology Assessment Committee issued a report on atropine for preventing myopia progression in children. The group reviewed 17 studies, of which eight were level I or II, and concluded that lower doses of atropine were slightly less effective than higher doses but were associated with less myopic rebound and fewer side effects.

“One caveat about the studies, however, is that the most robust research was carried out in Asian populations,” Dr Tan said.

Among currently ongoing studies, three are being conducted in the United States.
	
	

7 pearls for penetrating keratoplasty in pediatrics 


	More recently, the Low-concentration Atropine for Myopia Progression (LAMP) study compared atropine 0.01%, 0.025% and 0.05% versus placebo in children with myopia. 

Results collected after 2 years indicated that the highest concentration studied was most effective. 

Dr Tan observed that the efficacy of the 0.01% concentration in ATOM2 for reducing refractive change was more similar to that seen in the LAMP group treated with atropine 0.025% while the effect of the 0.01% concentration on axial length in ATOM2 almost equaled that achieved using the 0.05% concentration in LAMP. Pupil dilatation was also almost twofold greater in the ATOM2 atropine 0.01% group than in the atropine 0.01% group in LAMP. 

“It appears the effect of atropine differs in different formulation. The formulation used in LAMP was different than the ATOM formulation. Yet in ATOM-J, a study done in Japan, benefit was observed using the ATOM formulation of atropine 0.01%, but it was not as effective as the same formulation in ATOM2,” Dr Tan concluded. 

“We do not know yet what the best formulation will be. More studies are needed, and certainly there are a lot ongoing.”
	
	

This article is based on a presentation given by Dr. Tan at AA0 2019 in San Francisco, CA, USA. He is a consultant to pharmaceutical companies sponsoring studies of atropine treatment for myopia progression. 

Articles

Effects of atropine for controlling myopia progression in children 

This article was reviewed by Dr Frank G. Holz.

A proposed biosimilar to ranibizumab (FYB201, bioeq) demonstrated similar clinical efficacy, safety, and immunogenicity as a treatment for newly diagnosed subfoveal neovascular age-related macular degeneration (AMD) compared with reference ranibizumab (Lucentis, Roche/Genentech), said Dr Frank G. Holz.

Outcomes of patients treated with the reference ranibizumab and biosimilar were investigated in the prospective COLUMBUS-AMD trial. Holz presented the research at the 2020 virtual meeting of the American Academy of Ophthalmology.

“Biosimilars are less-expensive alternatives to reference biologic medicines. To receive marketing approval, biosimilars need to undergo comprehensive studies demonstrating high similarity with the reference biologic in all critical quality attributes, including physical, chemical, and biological properties,” said Holz, professor and chair, Department of Ophthalmology, University of Bonn, Bonn, Germany.

“The COLUMBUS-AMD study investigated the clinical equivalence of the biosimilar candidate FYB201 and reference ranibizumab," Holz added. "The findings of this study demonstrated the biosimilarity of FYB201 and reference ranibizumab with regard to efficacy as well as safety in patients with newly diagnosed neovascular AMD. They suggest that FYB201 may offer a new, high-value treatment option for patients with neovascular AMD.”

COLUMBUS-AMD enrolled patients age 50 years and older with subfoveal or juxtafoveal choroidal neovascularization (CNV) with foveal-involving leakage related to the CNV activity. Eligible patients needed to have foveal center point (FCP) retinal thickness ≥350 µm on spectral-domain OCT, a total lesion area ≤12 MPS disc areas, total CNV area ≥50% of total lesion area, and BCVA between 20/32 and 20/100 in the study eye.

The patients were randomly assigned 1:1 to receive monthly intravitreal injections of FYB201 0.5 mg or reference ranibizumab 0.5 mg for up to 48 weeks. The primary endpoint was change from baseline BCVA after 8 weeks. Key secondary endpoints included change from baseline BCVA at 48 weeks and change from baseline FCP retinal thickness at 48 weeks, as well as safety and immunogenicity.

A total of 477 patients were randomized to the two treatment arms. The two groups were well balanced at baseline with respect to median age (76 years), gender distribution (~44% male), and distribution of BCVA.

The study met its primary endpoint, showing that the 90% confidence interval for the change from baseline in ETDRS BCVA after 8 weeks was within the predefined equivalence margin. The analysis of least squares mean change in BCVA showed improvements of 5.1 ETDRS letters in eyes treated with FYB201 and 5.4 ETDRS letters in eyes treated with reference ranibizumab. The least-squares mean difference between groups of study eyes was -0.4 ETDRS letters with a 90% confidence interval of -1.6 to 0.9 ETDRS letters; the predefined equivalence margin was -3.5 to 3.5 ETDRS letters. At all follow-up visits, mean study eye BCVA and mean change from baseline in study eye FCP retinal thickness were highly similar between the groups of eyes treated with FYB201 and reference ranibizumab.

The overall safety profiles were also highly similar for the two study groups. Rates of any adverse event, drug-related adverse events, and serious drug-related adverse events in the FYB201 group were 64.7%, 8.4%, and 1.3%, respectively; corresponding rates in the reference ranibizumab group were 69.9%, 10.5%, and 1.3%, respectively. All-cause treatment-emergent intraocular inflammation occurred in 8.4% of eyes in both groups; the rate of treatment-emergent intraocular inflammation considered related to the investigational medicinal product was 0.8% in both groups. The types of ocular adverse events occurring in the two treatment groups were also similar, and most adverse events in both groups were mild or moderate in severity.

“No clinically relevant differences in safety profiles were identified between the treatment groups,” Holz said.

The immunogenicity analyses characterized the development of anti-drug antibodies and neutralizing antibodies and showed FYB201 and reference ranibizumab had comparable immunogenicity profiles. The rate of anti-drug antibody development was 5.9% in both treatment groups, and the ADA titers were also similar in the two groups. A single patient in the FYB201 group developed neutralizing antibodies between week 24 and week 48.

Holz receives research grants from bioeq/Formycon, and research grants, and honoraria for consultancy from Novartis (not related to the COLUMBUS-AMD study reported here).

Prospective randomised trial demonstrates clinical equivalence of biosimilar and reference ranibizumab

What a proposed biosimilar may bring to subfoveal wet AMD 

This article was reviewed by Bennet J. McComish, PhD


	
	In the largest study of its kind in keratoconus published so far, researchers conducting a genome-wide association study found a region of chromosome 11 in which multiple genetic variants were significantly more common in keratoconus patients than in unaffected individuals.
	
	Functional annotation of the associated variants indicated that several of the genes in the identified locus are likely involved in apoptotic pathways.

The findings were published in the February issue of 

2020;138(2):174-181.] Bennet J. McComish, PhD, research fellow, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia, is lead author of the article. 
	
	

Microscopy study suggests stem cell success in keratoconus 

“Our study, which was an international collaboration between groups in Australia, the United States, and the United Kingdom, aimed to identify genetic variants involved in the risk of developing keratoconus,” he said. “This information will allow us to better understand the biochemical pathways that are disrupted in keratoconus. It will help in the identification of potential therapeutic targets for this disease that is relatively common and can cause severe visual impairment.”

Dr. McComish said the region of chromosome 11 that researchers identified contains at least five protein-coding genes.

“The next step will be to determine which of those genes is implicated in the disease, recognizing that other genetic variations nearby can ‘hitchhike’ with the variants that cause the disease,” he said.  

Data used for the study were collected from individuals seen between January 2006 and March 2019 at eye clinics in Australia, the United States, and Northern Ireland.
	
	First, in a discovery phase, data were analyzed from 522 Australians with keratoconus and 655 unaffected individuals representing a control group. Subjects for the control group were taken from cohorts of the Australian Blue Mountains Eye Study and a previous study of glaucoma. 
	
	

Estimating the total corneal power in keratoconus patients 

Genotyping for 551,839 variants was done using the HumanCoreExome single-nucleotide polymorphism (SNP) array (Illumina). The SNPs with P values <1.00 x 10

 that were identified in the discovery cohort were assessed in three independent replication cohorts using the MassARRAY System (Agena Bioscience). 

The replication cohorts included 818 affected subjects with keratoconus and 3,858 unaffected controls. They were comprised of individuals included in a previous keratoconus GWAS data set from the United States, a cohort of subjects with keratoconus and unaffected controls from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. 

In the discovery cohort as well as in the three replication cohorts, the majority of keratoconus subjects were males (55% to 61%) and mean age for the cases in each cohort ranged from 35 to 45 years. The proportion of males among controls in the discovery cohort was greater than in the replication cohorts (47% versus ~38%). Mean age of the controls in all four cohorts was 17 to 28 years older than the mean age of their keratoconus counterparts. 

Gene therapy offering hope for retinal, corneal patients 


	The association analysis in the discovery cohort identified two novel loci with genome-wide significance. One of the novel loci was located on chromosome 11 at rs61876744 in patain-like phosphoplipase domain-containing 2 gene (

), and it reached genome-wide significance in an analysis of all four study cohorts. The other novel loci was on chromosome 22 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (

 locus reached significance in the replication cohorts, despite the fact that the 

 locus had the strongest association in the discovery cohort. When the data from the discovery cohort and the three replication cohorts were combined, 12 SNPS at the novel 

 locus were found to be associated with keratoconus at genome-wide significance. 

Blazing a new trail in gene therapy for retinal disease 


	Discussing their findings, the researchers noted that the function of the protein encoded by the lead SNP, which was located in an intron of 

, is to catalyze the initial step in triglyceride hydrolysis.
	
	Stating that there is no obvious connection between this biochemical pathway and keratoconus, they observed that the closest gene to an association signal is not necessarily the causative gene. 

“Other genes in the identified region are known to be involved in regulating apoptotic cell death, a process that has been suggested previously by other authors to be part of the mechanism underlying the development of keratoconus,” Dr. McComish said. “This finding will help focus future studies on the role of these genes in keratoconus.”
	
	

Research targets precision dosing for gene, cell therapy 


	The older mean age of the control cohorts compared to the case cohorts represents a possible study limitation. Because of the demographic difference, it will be important to assess the identified loci for age-associated effects in future studies, they wrote.
	
	

Dr. McComish has no relevant financial disclosures related to this topic. 

Study identifies genetic loci associated with keratoconus 

Performing in certain cases at presentation is better than waiting for progression

Findings from studies investigating the efficacy and safety of corneal collagen crosslinking (CXL) for keratoconus in paediatric-age patients and developmentally delayed adults and the consequences of leaving their ocular disease untreated provide a solid evidence base for offering CXL to these populations, said Ken K. Nischal, MD.

“In the United States, CXL is only approved for the treatment of progressive keratoconus in patients aged 14–65 years, and so it may not be offered to younger children even if indicated,” said Dr Nischal, professor of ophthalmology and Chief, Division of Pediatric Ophthalmology and Strabismus, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.  

“My take on this issue is that technology should be for those who cannot advocate for themselves or who are the most vulnerable. Those individuals are the children and developmentally delayed adults.
	
	In fact, there is mounting evidence that CXL should be offered to children at presentation rather than waiting for progression.”

Keys to assessing true crosslinking outcomes

Addressing the aggressive natural history 


	Multiple published studies demonstrate that keratoconus progresses at a rate that is much faster in children than in adults and that CXL arrests disease progression in paediatric patients, said Dr Nischal. 

Discussing some of these papers, he cited a study by Chatzis and Hafezi that reported a progression rate of 88% after 1 year of follow-up in a series of 59 eyes of 42 children awaiting CXL for keratoconus.


	
	Another study by Leon-Mesplie et al. showed that children who did not have CXL for keratoconus had a sevenfold increased risk of requiring a keratoplasty compared to adults.

“If you don’t want to do CXL in a child, you certainly do not want to have to perform penetrating keratoplasty considering the extra problems that it brings in terms of operative and postoperative issues,” Dr Nischal said.
	
	

Traversing the CXL pathway: Where do we go from here?

Other papers in the peer-reviewed literature show the safety and benefit of CXL for keratoconus in paediatric patients.
	
	In what is the largest published study to date, Padmanabhan et al. analyzed data from 194 eyes of 153 children aged 8–18 years that underwent CXL for documented progressive keratoconus.


	
	Of the 194 eyes, 142 had CXL using the standard Dresden protocol and 52 were treated using hypoosmolar riboflavin.

The CXL was associated with keratometric flattening and stabilisation of pachymetry during follow-up extending to 6.7 years. Of the total cohort, 59 eyes were followed for longer than 4 years, and reversal of keratometric flattening occurred in 14 (24%) of those eyes. 

“Interestingly, however, the flattening did not correlate with significant changes in vision or corneal pachymetry,” Dr Nischal said.
	
	

Towards a customised treatment of patients with keratoconic eyes

Findings from a study by Mazzotta et al. suggest that regression after CXLmay be more likely in patients with severe allergy who are eye rubbers.


	
	These investigators reported outcomes for 62 eyes of 47 patients aged 8–18 years who underwent CXL and represents the report with the longest post CXL follow-up for a paediatric population. 

The outcomes were stable at 10 years in 80% of eyes. A 2 D increase in mean keratometry occurred in four eyes of two patients who had severe ocular allergy and were eye rubbers, but stability was achieved after repeat CXL. No other patients in the series needed a repeat treatment because of CXL failure.

Two papers have reported on performing CXL for keratoconus in developmentally delayed patients.

“These individuals, who often have Down syndrome, already have challenges. Not performing CXL and therefore leaving them to possibly develop hydrops from progressive corneal thinning and lose vision makes their lives and the lives of their families much worse,” Dr Nischal said.
	
	

Doing justice to corneal irregularities 


	Reluctance to perform CXL in children and developmentally delayed adults may be partly due to concern that they will not remain still during a procedure performed using local anaesthesia.
	
	In addition, children and developmentally delayed adults may not comply with instructions to avoid eye rubbing that not only increases the risk of regression over time but also the chance for infection following the procedure. 

To overcome these potential problems, Dr Nischal said that he performs CXL in most paediatric patients and developmentally delayed adults under general anaesthesia with a regimen that will result in complete paralysis.

“If there is not complete paralysis, the eye may roll up during the UV light application, leaving me grabbing for forceps to try to hold the eye in place,” he explained.
	
	

Facing challenge of corneal infection management in operated eyes 

Dr Nischal said he uses integrated intraoperative OCT (Carl Zeiss Meditec) to assess adequacy of the riboflavin soak. An OCT scan prior to the soak allows for baseline evaluation and after the soak there is a visible change in reflectivity on the OCT.
	
	The OCT is also used after UV exposure: “If I see a clear interface after the UV light application, I know I am going to get a good result, but I do not yet have enough follow-up to know what the outcome is in cases where I cannot see the interface,” Dr Nischal stated.

To protect the eye in the early post-treatment period while the epithelial defect is healing, he usually places a temporary central tarsorrhaphy for 2 days and prescribes topical moxifloxacin six times daily to be applied at the medial canthus. 
	
	

Budding technology could be an OCT analysis game-changer

“So far, we have not had any cases of infection, and the children seem comfortable with the tarsorrhaphy in place,” Dr Nischal said.

“Interestingly, patients who had CXL elsewhere with placement of a bandage contact lens reported much less pain and discomfort with their second eye procedure using tarsorrhaphy.
	
	One case involved a developmentally delayed patient whose parents were very frightened about the child tolerating the second eye procedure. The parents reported that, with the lids sutured shut, the child did not touch the eye and was very relaxed.”

In addition, Dr Nischal is aggressive with treatment for allergic conjunctivitis-related inflammation both pre- and post-CXL as a strategy to mitigate eye rubbing. Patients are also referred for behavioural therapy to reduce eye rubbing.
	
	


	Between July 2018 and September 2019, Dr Nischal performed CXL in 18 eyes of paediatric patients. 

All cases were done using the standard Dresden protocol.
	
	Sixteen cases were done using general anaesthesia, of which 14 had a temporary tarsorrhaphy placed and two had a bandage contact lens.
	
	Eight of the cases involving temporary tarsorrhaphy were in developmentally delayed or non-verbal children. Topical anaesthesia with post-CXL placement of a bandage contact lens was used in two eyes of healthy teenagers aged 15 years. 
	
	

Read more by Cheryl Guttman Krader, BS, Pharm

This article is based on a presentation given by Dr. Nischal at the American Academy of Ophthalmology 2019 meeting in San Francisco, California, USA. Dr. Nischal receives honorarium from Carl Zeiss Meditec, but has no other relevant financial interests to report. 

1. Chatzis N, Hafezi F. Progression of keratoconus and efficacy of pediatric corneal collagen crosslinking in children and adolescents. 

2. Leoni-Mesplie S, Mortemousque B, Touboul D, et al. Scalability and severity of keratoconus in children. 

3. Padmanabhan P, Rachapalle Reddi S, Rajagopal R, et al. Corneal colleagen cross-linking for keratoconus in pediatric patients: log-term results. 

4. Mazzotta C, Traversi C, Baiocchi S, et al. Corneal collagen crosslinking with riboflavin and ultraviolet a light for pediatric keratoconus: ten-year results. 

5. Koppen C, Leysen I.  Riboflavin/UVA cross-linking for keratoconus in Down syndrome. 

6. Sabti S, Tappeiner C, Frueh BE. Corneal
	crosslinking in a 4-year-old child with keratoconus and down syndrome. 

7. Lalgudi VG, Nischal KK. Pediatric corneal collagen crosslinking for keratoconus: not an experimental procedure.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

What a proposed biosimilar may bring to subfoveal wet AMD

Study identifies genetic loci associated with keratoconus

Corneal collagen crosslinking imperative in paediatric keratoconus

Effects of atropine for controlling myopia progression in children