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

Cheryl Guttman Krader, BS, Pharm

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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. 

Articles

Study identifies genetic loci associated with keratoconus 

 presents a comprehensive discussion of current knowledge regarding the disease state, raises important questions to be addressed in future research and underscores the idea that AMD is not a single entity but instead represents a disease spectrum with distinct phenotypes that appear to have different underlying risk factors and pathogenic pathways.

 was written by invitation from the journal’s editors and represents joint efforts by an international expert panel organised by Emily Y. Chew, MD, PhD, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute at the National Institutes of Health in Bethesda, Maryland. The paper covers epidemiology; mechanisms/pathophysiology; diagnosis, screening and prevention; management; and quality of life, and it cites 280 references.

Age-related macular degeneration: treatment overview (video)

Monika Fleckenstein, MD, a professor of ophthalmology at John A. Moran Eye Center at the University of Utah in Salt Lake City, is the first author of the work. Although there have been several recent review articles on AMD, Fleckenstein told 

™ that she believes this paper stands out for the depth and breadth of the information it contains.

“Although our paper, which is a review article, does not present new original research, we believe it highlights some important new concepts about AMD and topics for future investigations,” she said.

Ray tracing and IOL modelling in AMD patients (video)

Moreover, Fleckenstein added that her team believes the global overview of AMD provided in their paper will be useful for all ophthalmologists, ophthalmologists in training and physicians in other fields of medicine in addition to anyone with a special interest in AMD.

“We hope that our emphasis on the idea that AMD comprises diverse pathological conditions will be thought-provoking for basic and clinical scientists as they plan new research that ultimately will lead to improved care and better quality of life for patients with AMD,” she added.

Fleckenstein pointed out that when the article was solicited, the journal editors asked that it describe a model of AMD. However, complying with this request challenged the writing group because the exact interactions of pathophysiological events that may culminate in different AMD types remain to be elucidated.

“We know there are different phenotypes and stages in this bucket of AMD, and because of accumulating evidence, we are more and more convinced there are different dominant mechanisms for their development,” Fleckenstein said.

Ang-2/VEGF-A inhibition synergistic effect in DME and AMD (video)

For example, she noted that current information indicates that risk factors for the development of geographic atrophy differ from those associated with progression of the atrophic lesions. Knowledge of these differences is important for investigators, as it indicates a need to focus on different targets for preventive versus therapeutic interventions.

In discussing neovascularisation in AMD, the paper highlights new concepts and terminologies that have emerged thanks to clinicopathological correlations that have been refined through advances in imaging techniques. First, the paper uses the term 

based on the fact that not all neovascularisation in the area of the macula arises from the choroid.

Non-viral gene therapy eases treatment burden in wet AMD

In addition, the article reviews evidence of different types of MNV, some of which seem to protect against AMD progression.

“This latter concept was first put forth decades ago by histopathologists but has only recently gained full attention because newer imaging technologies have enhanced our ability to visualise different subtypes of MNV in vivo,” Fleckenstein said. “Indeed, several studies implementing high-resolution retinal imaging have shown that rates of dry AMD progression differ depending on the presence of certain MNV subtypes.”

Fleckenstein added that the observations may lead to the identification of new therapeutic targets and also argue against interventions that aim to eliminate all MNV.

One goal of developing new consensus terminologies for distinct manifestations of AMD is to provide a complete view of pathological changes that occur in the disease.

Fleckenstein noted, however, that it is a task not easily done. For example, although the term 

recognises the fact that not all AMD-related neovascularisation originates from the choroid, it does not account for the fact that AMD can also be associated with neovascularisation in the peripheral retina.

Brolucizumab for neovascular AMD: Safety guidance and clinician perspectives

“It became clear to me while working on this project that it is not always possible to find all-inclusive terms that also reflect the range of experts’ opinions,” she said. Even if a group comes to a consensus about a particular classification system or preferred term, other specialists in the field may not agree.

“But it is the open-minded discourse that will advance our field,” she noted. “We also have to realise that terminologies are always subject to flux as new information emerges.”

Fleckenstein receives grants from Heidelberg Engineering, Genentech/Roche, Novartis and Optos; personal fees from Bayer, Heidelberg Engineering, Genentech/Roche and Novartis; and nonfinancial support from Carl Zeiss Meditec, Heidelberg Engineering and Optos outside the submitted work.

1. Fleckenstein M, Keenan TDL, Guymer RH et al. Age-related macular degeneration. 

2021;7(1):31. https://doi.org/10.1038/s41572-021-00265-2

2. Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D. The progression of geographic atrophy secondary to age-related macular degeneration. 

 2018;125(3):369-390. doi: 10.1016/j.ophtha.2017.08.038. Epub 2017 Oct 27. PMID: 29110945

Why investigators are recognising AMD as a disease spectrum rather than a single entity.

Expanding the definition of AMD

Results from 5 years of follow-up show that minimally invasive 

 (MIGS) with simultaneous implantation of two trabecular microbypass stents (iStent Inject, Glaukos) combined with phacoemulsification is safe and provides durable moderate lowering of intraocular pressure (IOP). It also reduces the burden of topical ocular hypotensive medications, according to Dr Karsten Klabe.

Dr Klabe is in private practice at the Breyer, Kaymak and Klabe Eye Surgery Practice in Düsseldorf, Germany, and is a partner at the International Vision Correction Research Centre of the Heidelberg University Hospital. “A number of MIGS procedures are now available, and [although] they have shown encouraging initial results in pre-marketing clinical trials, data are needed to understand their long-term efficacy and safety,” said Dr Klabe.

Personalising glaucoma surgery: The role of MIGS

“Our experience using combined iStent Inject implantation and 

 shows that with selection of appropriate candidates, patients will rarely need further intervention for their glaucoma, and the majority can become medication-free,” he said. “Considering the latter benefit, adding the iStent Inject when patients need cataract surgery addresses the adherence issues we face when prescribing glaucoma therapies and their potential to cause ocular surface disease so that patients have a higher quality of life.”

Dr Klabe’s study of outcomes after combined cataract surgery with implantation of the iStent Inject was a retrospective review that included 164 eyes in 103 patients. The cohort had a mean age of 75.4 years and the majority were male. Primary open-angle glaucoma was the predominant diagnosis (82%) and the remaining eyes had pseudoexfoliation glaucoma (18%).

Eliminating the potential land mines in glaucoma surgery

Preoperatively, the 164 eyes had a mean IOP with medication of 18.5 mmHg. The average mean deviation on the visual field was -6.19 dB MD and mean cup/disc ratio was 0.59.

Twenty-nine eyes (18%) had previously been treated with selective laser trabeculoplasty (SLT), and eight eyes had undergone previous surgery, which included placement of the Xen Gel Stent (Allergan), canaloplasty, trabeculectomy or iridotomy. All of the previous interventions were performed more than 3 months prior to the combination cataract/MIGS procedure.

Endoscopic cyclophotocoagulation adds cumulative advantage to MIGS

Of the 164 implanted eyes, 157 had 24 months of follow-up; 129, 85 and 61 eyes were seen at 26, 48 and 60 months, respectively. Mean IOP decreased to 16 mmHg at 1 month after surgery and to 15.5 mmHg at month 6, and stabilised at that level (±0.5 mmHg) for the remaining follow-up duration.

At baseline, patients were taking a mean of 1.47 medications to lower IOP (range 0–4). Throughout follow-up, no patients were taking more than two medications and the mean of medications used daily ranged from 0.17 to 0.23 without any evidence of an increase over time.

The two microstents are injected into the eye using a specially designed applicator. (Image courtesy of Dr Karsten Klabe

Highlighting the safety of the combination procedure, Dr Klabe reported that there were very few complications in the series. The majority were minor and related to the MIGS procedure. They included hyphaema in 11 eyes (6.7%), persistent hypotony (IOP < 10 mmHg for more than 1 month) in two eyes (1.2%) and iris incarceration in two eyes (1.2%). In addition, there were seven cases (4.3%) of stent occlusion.

“The cases of occlusion were observed later than 3 months after surgery and were related to implantation that was too deep,” Dr Klabe said. “It is very important to hold the injector in place without pushing it forwards during implantation. However, the introduction of the iStent [inject] with a wider flange solved the risk of over-implantation.”

Study examines pairing phacoemulsification with implantation of stents

Data regarding the need for further glaucoma surgery provided further evidence of the efficacy of the combination surgery. Over the 5 years of follow-up, only seven eyes (4.3%) underwent a second procedure: placement of the Xen Gel Stent in three eyes, implantation of the Preserflo MicroShunt (Santen) in two eyes, SLT in one eye and cyclophotocoagulation in one eye.

The two microstents are pre-loaded in a specially designed applicator in a procedure that has a short learning curve but requires minimal additional settings and instruments, according to Dr Klabe. “When combined with phacoemulsification, the glaucoma portion of the procedure can be done either prior to or after the cataract surgery, according to the surgeon’s preference,” he said.

SMILE procedure offers low enhancement rate after nomogram adjustment

Dr Klabe explained that he prefers to perform the stent implantation at the end of the surgery, noting that the deep anterior chamber offers excellent visibility and lowers the risk of iris damage. “On the other hand, the main incision in my cases is only 2.2 mm and prevents the loss of [the] ophthalmic viscosurgical device and flattening of the anterior chamber,” he said. “Use of a Vold Gonioprism (Volk Optical) with retention ring may be helpful because of the low pressure on the cornea that guarantees good visibility.”

Dr Klabe is a consultant/adviser to, study investigator for and recipient of travel stipends from Glaukos and other companies that market devices for MIGS.

Retrospective review highlights the sustained efficacy of combination procedure.

Combined MIGS and cataract surgery option offers positive results

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

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Expanding the definition of AMD

Combined MIGS and cataract surgery option offers positive results

What a proposed biosimilar may bring to subfoveal wet AMD

Study identifies genetic loci associated with keratoconus