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

The results have been published in the peer-reviewed journal 

Investigative Ophthalmology and Visual Science.

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

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

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

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

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

Moreover, Dr Pierscionek said in the release that the research has shown that there is a remarkable difference and improvement in optics between eyes with the same type of cataract that were treated with the compound compared to those that were not.

“Improvements occurred in some types of cataract but not in all indicating that this may be a treatment for specific cataracts,” she concluded in the statement. “This suggests distinctions may need to be made between cataract types when developing anti-cataract medications. It is a significant step forward towards treating this extremely common condition with drugs rather than surgery.”

1. Pierscionek, B; et.al; Oxysterol compounds in mouse mutant αA- and αB-crystallin lenses 2 can improve the optical properties of the lens. Investigative Ophthalmology & Visual Science. Published May 16, 2022.

Articles

An investigator at Anglia Ruskin University is leading work on an anti-cataract drug, which has had positive results in lab tests.

Approaching pharmaceutical treatment for cataracts

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

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

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

Dry Eye Syndrome is a chronic disease that affects the productivity and quality of life of 1.52 billion people worldwide.

 The COVID-19 pandemic has further exacerbated the problem, as prolonged time in front of screens is a risk factor for the disease.

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

George Oursler, senior vice president anterior segment at Ora, noted that the company has been passionate about addressing the challenges of DES and honoured to be working with the BRIM team to bring this treatment closer to patients.

“The PDSP technology platform is unlike any currently available treatment for dry eye, and the evidence from studies completed thus far show strong potential that BRM421 can repair the corneal damage and alleviate the DES symptoms rapidly,” he said in the news release. “We are excited to leverage the deep expertise Ora has in bringing new ocular health therapies to market to shape the upcoming Phase 3 trials for BRM421 and advance this novel DES therapy closer to approval.”

Dr Haishan Jang, president and CEO of BRIM, explained that the new partnership builds on the success of the companies’ previous collaboration for Phase 2 trials and will help to speed the progression of BRM421 through late-stage clinical development towards regulatory filing.

“BRIM’s translational science expertise, together with Ora’s extensive and successful track record in ophthalmic product development, will undoubtedly accelerate our timelines,” he said in the news release. “With this new agreement in place we intend to initiate Phase 3 studies in Q4 this year and are thrilled at the prospect of bringing this potentially transformative treatment to patients sooner.”

DES currently has no cure and requires continual disease management. Artificial tears with demulcents can retain surface moisture and immune modulators can help to control inflammation, allowing the body’s natural healing processes to repair damage. However, for moderate to severe patients, these types of treatments are often not enough to control discomfort unless there is a way to further speed up the healing process.

“Regenerative peptide, BRM421, has a unique mechanism of action which stimulates the proliferation and differentiation of corneal limbal stem cells which, as a result, speeds up corneal repair and heals ocular wounds in DES patients.

 BRM421 is on track to become the first DES treatment with rapid and total relief,” concluded Dr Jang.

1. Dry Eye disease clinical markets 2021-2029: Marketed and Pipeline Drugs, clinical trials, upcoming and regulatory events, epidemiology, licensing and acquisition deals, drug revenues. Dry Eye Disease Clinical Markets 2021-2029: Marketed and Pipeline Drugs, Clinical Trials, Upcoming and Regulatory Events, Epidemiology, Licensing and Acquisition Deals, Drug Revenues. 

https://www.prnewswire.com/news-releases/dry-eye-disease-clinical-markets-2021-2029-marketed-and-pipeline-drugs-clinical-trials-upcoming-and-regulatory-events-epidemiology-licensing-and-acquisition-deals-drug-revenues-301328151.html

2. Ping-Yen Yuang, MD, Yeou-Ping Tsau, et.al; Topical BRM421 Ophthalmic Solution improves signs and symptoms of moderate to severe dry eye patients in clinical trials. Investigative Ophthalmology & Visual Science June 2021, Vol. 62, 1335.

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

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

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

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

The technology is especially useful in what Dr Mullick describes as “confusing” cases, which comprise about 35% of those that pass through her clinic. For example, upon examination, one patient had a thin cornea but no keratoconus; another had a suspicious presentation, but the biomechanics were normal; and yet another had normal topography but suspicious biomechanics. 

This raises the question: should physicians rely on the corneal topography or the biomechanics in such cases? This question spurred the development of PS-OCT, which can image the spatial distribution of fibril structures and their orientation.

As Dr Mullick explained, “The arrangement of collagen fibres in normal corneas exhibits a checkered pattern centrally. In the images, the presence of dark blue/purple indicates the least phase retardation: that is, the least alteration of polarised light, due to the uniform arrangement of the collagen fibres. This indicates a very healthy cornea.”

When corneas are diseased, however, irregular organisation of the collagen fibres can be seen, with more alteration of the polarised light; this indicates higher phase retardation, as seen by the warmer colours in the image.

Dr Mullick and her colleagues studied 135 corneas prospectively: i.e., 50 that were healthy, 50 with keratoconus and 35 suspicious corneas. All patients underwent corneal tomography, corneal biomechanics and epithelial mapping in addition to biomicroscopy, fundus evaluation and refraction.

The evaluations were followed by PS-OCT. The results were categorised based on the topographic and biomechanical analyses followed by 

 analysis of the phase retardation (PR) distribution. The Belin-Ambrosio enhanced ectasia display (BAD) software, which helps in the early detection of subclinical keratoconuschanges, was used with the inbuilt Oculus HR Pentacam camera system.

Dr Mullick provided some examples of representative cases. She reported that the 

 imaging by PS-OCT showed normal topography in two cases, but another case yielded a suspicious BAD deviation value (BAD-D).However, the checkered arrangement in the centre of the image indicated that the two corneas were healthy and therefore would be suitable candidates for refractive surgery.

A third case had normal BAD-D and suspicious biomechanics; this patient had a partial loss of the checkered arrangement. In this case, refractive surgery was deferred. The fourth case had a thin cornea and no keratoconus, but there was partial loss of the checkered arrangement.

In the fifth and sixth cases, with keratoconus and post-SMILE ectasia, respectively, there was a complete loss of the checkered arrangement, which indicated that these were weak ectatic corneas with weak collagenous arrangements.

This approach has facilitated the ability to diagnose disease earlier before it becomes apparent on topography. “PS-OCT can clearly identify differences in collagen fibre distributions between healthy and keratoconic corneas. Suspicious corneas had a unique distribution of collagen, which indicated early changes before they were detected on topography,” Dr Mullick commented.

She added: “The imaging technology can help diagnose keratoconus even in cases that have normal or borderline suspicious topography findings, and therefore can be an excellent screening modality.”

The technology can also be used to screen candidates for refractive surgery; identify forme fruste keratoconus; monitor keratoconus progression or follow cross-linking outcomes; perform post-graft imaging; or diagnose retinal disorders.

This article was adapted from Dr Mullick’s Subspecialty Day presentation at the 2021 American Academy of Ophthalmology annual meeting, New Orleans, Louisiana, United States. Dr Mullick has no financial interest in this subject matter.

Polarisation-sensitive optical coherence tomography has facilitated early diagnosis of disease before it becomes apparent on topography. 

The missing link in the recognition of corneal abnormalities 

According to the clinicaltrials.gov database, there are around 2,000 gene therapies currently under investigation worldwide in many areas of medicine. In recent decades, the discipline has rapidly evolved.

Whilst the focus of most gene therapies has so far been on rare diseases, many additional drugs/products are currently being studied to treat disorders such as cancer as well as genetic and infectious diseases. And around 20 gene therapies are already available in the United States, having received Food and Drug Administration (FDA) approval.

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

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

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

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

In 2017, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) became the first FDA-approved ocular gene therapy. Also approved in Europe (since 2018), it is used to treat certain inherited retinal diseases such as 

-related Leber congenital amaurosis or retinitis pigmentosa.

As mentioned already, gene therapies focus on monogenetic diseases. The approach becomes much more complicated for diseases with many pathways involved, such as age-related macular degeneration (AMD). Hence, current methods focus on gene augmentation and/or suppression to enhance or reduce the production of a molecule that plays a crucial role in the pathogenesis of the disease.

In wet AMD, this is vascular endothelial growth factor (VEGF). Its antibody (anti-VEGF) needs to be applied on a monthly basis, which may lead to both clinical and adherence problems. One way to overcome this is a surgical intervention such as the implantation of a slow-release device. An alternative would be the augmentation of anti-VEGF-production using a genetic approach.

One candidate that is currently being studied is RGX-314 (Regenxbio). This drug is delivered subretinally or suprachoroidally. It contains a novel adeno-associated viral vector (AAV8) and is currently in development for wet AMD, diabetic retinopathy and other retinal diseases.

As described above, the cells are transfected, which delivers the information to produce a protein. This protein is designed to neutralise VEGF and, by doing so, modify the pathway for the formation of new leaky blood vessels and retinal fluid accumulation.

Both approaches, subretinal and suprachoroidal, are surgically challenging. However, the suprachoroidal method, which our group used for the application of other drugs more than a decade ago, has been redesigned and appears to be a safe way to apply such a drug.

The positive interim results of two trials of RGX-314 (AAVIATE and ALTITUDE) using in-office suprachoroidal delivery were presented by Dr Robert L. Avery at the most recent meeting of the American Academy of Ophthalmology. The studies are including wet AMD and diabetic retinopathy patients without centre-involved diabetic macular oedema.

Another drug candidate in development is ADVM-022 (Adverum Biotechnologies), an adeno-associated virus vector encoding aflibercept. Results to date have shown that a single intravitreal administration of ADVM-022 is able to provide a safe and effective long-term treatment option for both wet AMD and diabetic macular oedema.

Looking at dry AMD, the approach is similar. Rather than focusing on genes that are responsible for the disease, we are trying to produce or antagonise factors that are part of the pathogenetic cascade. Inflammation has been shown to play a crucial role in the pathogenesis of dry AMD.

One way to tackle inflammation is by increasing the production of complement factor I (CFI), also known as C3b/C4b inactivator (a protein that regulates complement activation). Doing so has been shown to reduce complement activity and thereby inflammation.

About 3% of patients suffering from dry AMD have CFI mutations, with lower CFI levels giving a higher risk of dry AMD. GT005 (Gyroscope Therapeutics) is a AAV2 vector that delivers a plasmid construct expressing normal CFI; it is currently under investigation with promising results and no significant side effects so far, although the drug does need to be applied subretinally.

As described, clinical studies of promising ocular gene therapies are underway. However, safety remains a concern in this area of therapeutic medicine, where retinal pigment epithelium (RPE) changes and inflammatory reactions can take place. Thankfully, there have been some reports that these potential side-effects can be successfully controlled by topical steroids.

Until now only patients who have been heavily pre-treated have been included in trials. As well as the need to conduct intensive safety assessments, before these new gene therapy approaches can be used on regular basis in real-world settings, Phase 3 trials need to be completed and surgical procedures taught.

And so, while we are entering a new era of drug therapy, with gene therapy having the potential to change the way many diseases are treated (good news for our patients), there is still much work ahead. Both drug safety and drug delivery issues present major challenges that need to be addressed.

One promising future approach lies in the CRISPR-Cas9 gene-editing tool, which has recently been introduced for the treatment of a hereditary human disease. It functions rather like a molecular scissor to snip parts of the DNA: in this way, we can insert, delete or modify genes.

After identifying the defective genes, this exciting technology will provide the next step in gene therapy. We are already underway and have identified the defective genes in other hereditary diseases. Thus, this new technology will first be used in diseases with a clearly defined genetic signature.

Dr Augustin is professor of ophthalmology and chairman of the Department of Ophthalmology at the Karlsruhe Municipal Hospital, Germany. He has no financial disclosures related to this article.

Promising gene therapies in development are pinpointing steps in the pathogenic cascades involved in ocular diseases, such as VEGF for wet AMD and CFI for dry AMD.

Making strides in ophthalmology with modern gene therapy techniques 

A recent Phase 1/2a trial of an intravitreal treatment designed to treat diabetic macular ischaemia (DMI), BI-X (Boehringer Ingelheim), found the candidate to be well tolerated with no dose-limiting events and no drug-related adverse events, according to Dr Quan Dong Nguyen, a professor of ophthalmology at Byers Eye Institute at Stanford University School of Medicine in Palo Alto, California, United States.

DMI is defined as any disruption in retinal vascularity within the superficial and/or deep retinal plexus as seen on optical coherence tomography angiography, and it is a complication of diabetic retinopathy (DR). Currently, there is no treatment available that can prevent or stop progression of DMI. Dr Nguyen pointed out that the development of a treatment is important because it is a common complication that can have a profound impact on a patient’s vision.

BI-X works as an anti-ischaemia modulator of the human protein, semaphorin 3A, which blocks revascularisation in ischaemic retinas.

DMI patients enrolled in the Phase 1/2a study had previously been treated with laser for DR. The study has two parts, or ‘phases’, and all subjects treated with BI-X have received one intravitreal dose of the drug.

The non-randomised, open-label section of the study is complete. Three cohorts received 0.5-, 1- or 2.5-mg doses of the therapy; the cohorts included three, three and six subjects, respectively. The primary endpoint was the number of dose-limiting events, and the secondary endpoints were the numbers of drug-related and ocular adverse events.

According to Dr Nguyen, the best-corrected visual acuity (BCVA) improved slightly compared with baseline in the subjects assigned to 1 and 2.5 mg of BI-X. No dose-limiting, drug-related or serious adverse events occurred. Three subjects experienced ocular adverse events: specifically, subconjunctival haemorrhage and ocular hyperaemia, both in the 0.5-mg cohort.

One vitreous detachment occurred in the 2.5-mg cohort. Four procedural-related adverse events occurred: subconjunctival haemorrhage, ocular hyperaemia and temporary intraocular pressure increase in the 0.5-mg group, and mild pain after the procedure in the 2.5-mg group.

The findings in the three cohorts were similar. The main take-aways from the SRD study were that BI-X was well tolerated by subjects with DMI in all three dosing cohorts and that the BCVA showed signs of improvement compared with baseline in the 1- and 2.5-mg cohorts.

In the second, ongoing, single masked and randomised segment of the study, the BI-X cohort (20 subjects) will receive three 2- to 5-mg doses separated by 4-week intervals and 10 subjects are to receive sham injections.

The primary endpoint is the number of drug-related adverse events; the secondary endpoints are the number of ocular adverse events and the changes from baseline in the foveal avascular area size, BCVA and central retinal thickness.

“Discovering a treatment for DMI is a major challenge for many clinician-scientists, as DMI can lead to significant visual loss, even if the diabetic macular oedema is well controlled,” Dr Nguyen concluded. “It is our hope that BI-X can be among the first successful treatments for this devastating complication of diabetic retinopathy.”

This article is adapted from Dr Nguyen’s presentation at the American Academy of Ophthalmology Annual Meeting. Dr Nguyen has received research funding from Boehringer Ingelheim.

An ischaemia modulator has demonstrated it is safe and well tolerated in a Phase 1/2a trial in diabetic macular ischaemia patients.

Promising early data with intravitreal diabetic macular ischaemia candidate

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

Results from a retrospective study of patients treated with amniotic membrane transplantation (AMT) for Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) highlight the risk for long-term ocular complications and the need for ongoing management.

Reviewing outcomes in a series of patients who underwent AMT during the acute phase of SJS/TEN, the investigators found that ocular surface structures were often affected by chronic sequelae that led to dry eye disease (DED) as a common complication.

“AMT over the ocular surface for the treatment of ocular involvement in the acute phase of SJS/TEN was first described in 2002. Since then, it has become the gold standard, and there have been many efforts to intervene early and aggressively with AMT. However, management of chronic ocular sequelae is just as paramount because these patients are at risk for developing severe dry eye and ocular surface disease,” according to Dr Tatiana S. Zanganeh, a third-year ophthalmology resident at San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam Houston, Texas, and a captain in the United States Air Force.

“This management should be done by a cornea or DED specialist who has extensive knowledge of the available treatment options that include aggressive lubrication, topical or oral anti-inflammatory agents, serum tears, scleral contact lenses, or, if the condition is severe enough, total penetrating keratoplasty,” she added.

Outcomes using ocular AMT in the acute treatment of patients with SJS and TEN were evaluated by identifying patients with a histopathologically confirmed diagnosis admitted to Brooke Army Medical Centre at Fort Sam Houston between January 2006 and January 2020.

Of 112 patients admitted with SJS/TEN, 52 patients (102 eyes) were treated with ocular AMT. Management also included hourly topical lubricants, frequent topical corticosteroids, and antibiotics as clinically indicated.

Median time to AMT following onset of symptoms was 5 days (range, 3 to 6 days), and additional AMT was required for treatment of 64% of the eyes.

Follow-up of longer than 2 months from the date of initial AMT was available for 39 eyes of 20 patients.

Within the latter subgroup, TEN was the diagnosis for 17 patients, 2 were diagnosed with SJS, and 1 with SJS/TEN overlap. The 2 most common agents inciting the condition were antibiotics (n = 8) and antiepileptics (n = 8).

Visual acuity results at last visit for the eyes with chronic follow-up showed that 29 achieved BCVA of 20/40 or better. BCVA ranged between 20/40 and greater than 20/200 in 5 eyes and was 20/200 or worse in the remaining 5 eyes.

Complications involving the cornea and eyelid margin were seen in the majority of eyes at last follow-up.

There was a statistically significant reduction in the number of eyes with conjunctival involvement, although conjunctival complications were present in 14 eyes.

All eyes had involvement of eyelid skin at presentation compared with just 2 eyes at last follow-up.

Cornea complications at last follow-up included punctate epithelial erosions or epithelial defect, subjunctivization, and corneal scar, and some eyes required penetrating keratoplasty.

Conjunctival complications included punctate staining and scarring. Eyelid margin complications included forniceal shortening and meibomian gland dysfunction or trichiasis. Eyelid skin was normal in most patients, but some had mild scarring or lagophthalmos.

“No patients developed lagophthalmos, perhaps because eyelid skin sloughing was not deep enough to cause cicatrisation that would result in lagophthalmos,” Dr Zanganeh said.

A review of the chronic complications indicated factors contributing to the development of chronic DED in patients with SJS/TEN.

They include aqueous tear deficiency from lacrimal gland scarring leading to aqueous tear deficiency, decreased wettability of the corneal surface due to persistent punctate epithelial erosions or other corneal epithelial defects from limbal stem cell deficiency, and tear film instability arising from increased evaporative tear loss related to the destruction of mucin-producing conjunctival goblet cells and meibomian gland scarring.

Dr Zanganeh also described an approach for extending coverage of the involved tissues with AM.

Rather than using the self-retained cryopreserved amniotic membrane (Prokera; Biotissue) that only covers the cornea and perilimbal surface of the eye, a larger sheet of AM is used that can overlap the bulbar, palpebral, and forniceal conjunctiva as well as the eyelid margin.

The sheet of AM is secured to the eyelid skin with bolstered sutures and then accordion-folded into the forniceal spaces with a customizable symblepharon ring that is fashioned from sterile intravenous tubing.

Then, the sheet is draped over the entire ocular surface, folded into the opposite forniceal space, and draped over the opposite lid margin before it is secured to the eyelid skin.

“Originally, the procedure was done in the operating room with sedation, and it also resulted in suture trauma to the eyelid skin,” Dr Zanganeh concluded. “The technique has evolved, and the procedure can now be performed at the bedside under topical anaesthesia and using cyanoacrylate glue in lieu of sutures.”

Dr Zanganeh and her coauthors, Col Sheri L. DeMartelaere, MC, USA, and Col (Ret) Anthony J. Johnson, MC, USA, have no relevant financial interests to disclose.

Patients are at risk for developing severe dry eye and ocular surface disease.

Acute and chronic care required for eye with SJS/TEN ocular involvement

Over the past decade, minimally-invasive glaucoma surgery (MIGS) has revolutionised glaucoma management, offering a myriad of advantages such as minimal disruption of the eye’s natural anatomy and physiology, a shorter recovery period and an enhanced safety profile.

However, most MIGS approaches still alter the anterior chamber angle anatomy; for example, trabecular meshwork ablation using an electropulse or micro-trabecular bypass stents,which alter aqueous currents by creating an artificial pathway via one or two points of exit for aqueous humour.

In our practice we use canaloplasty to improve the flow of aqueous throughout the entire 360 degrees of the conventional outflow pathway without redirecting aqueous currents to a single point of exit. It offers a comprehensive approach by addressing all aspects of potential outflow resistance in the trabecular meshwork, Schlemm’s canal and collector channel systems, with proven safety and long-term efficacy in peer-reviewed studies.

Introduced in 2016, ab-interno canaloplasty is a physician-led refinement of traditional canaloplasty, entailing the intubation of Schlemm’s canal with a flexible microcatheter via a self-sealing, clear corneolimbal incision. This approach preserves the conjunctiva and thus can be used earlier in the treatment paradigm in cases of mild-to-moderate glaucoma. As an added benefit, it does not require a permanent implant in the eye.

We use the iTrack canaloplasty microcatheter (Nova Eye) and, more recently, the iTrack Advance. With an illuminated fibre optic tip, both devices provide continuous location feedback in addition to an internal guidewire mechanism that permits catheterisation of up to 360 degrees of the canal during a single intubation.

The ab-interno technique is based on the same principles as traditional canaloplasty and is defined as the 360-degree catheterisation of Schlemm’s canal to break obstructions and adhesions, followed by the subsequent viscodilation of Schlemm’s canal upon withdrawal of the microcatheter whilst injecting a high-molecular-weight hyaluronic-acid-based ophthalmic viscosurgical device (OVD).

This pressurised delivery of OVD dilates the canal, thus restoring the physiological aqueous outflow pathway. The tissue-sparing aspect of ab-interno canaloplasty allows future surgical options that rely on the preservation of the trabecular meshwork in patients who may need further intervention as the disease progresses.

This comprehensive approach makes ab-interno canaloplasty an effective treatment modality in a variety of glaucoma patients, including those with mild-to-moderate open-angle glaucoma (OAG) and those who are intolerant, non-compliant or unresponsive to anti-glaucoma medication.

Ab-interno canaloplasty can be performed either as a standalone procedure or combined with cataract surgery. Various studies have documented long-term efficacy for reduction of both IOP and anti-glaucoma medication burden along with a satisfying safety profile and low risk of severe complications up to 36 months following surgery.

The ab-interno technique is typically performed in cases of mild-to-moderate glaucoma and, to my knowledge, existing published literature does not incontrovertibly report clinical evidence with more advanced glaucoma stages. Furthermore, despite its minimal learning curve, familiarity with the gonioprism is a known challenge of all the MIGS procedures. In addition, the addition of the ab-interno canaloplasty procedure can add up to 10–15 minutes to traditional phacoemulsification.

I was one of the first surgeons to use ab-interno canaloplasty in Europe and I recently presented the results of our retrospective, monocentric, consecutive case series using the ab-interno surgical technique at the 2021 European Society of Cataract & Refractive Surgeons meeting in Amsterdam and published the 4-year results.

The study was conducted on 27 eyes of 22 patients with mild-to-moderate OAG experiencing insufficient IOP reduction or intolerance and non-compliance with glaucoma medication, also including a previously failed trabeculectomy. These patients underwent ab-interno canaloplasty with post-surgical follow-ups at 12, 24, 36 and 48 months.

The results were promising and demonstrated the efficacy of the procedure in reducing IOP and medication dependency, as well as patient complications. Mean IOP significantly reduced by 30% from baseline (

< 0.001), and the reduction was sustained 4 years postoperatively, from 19.8 ± 5.2 mmHg at baseline to 14.6 ± 3.0 mmHg at the last follow-up.

A significant reduction in mean medication usage was evident 4 years postoperatively as well, from 1.92 ± 1.00 at baseline to 0.89 ± 0.83, and we were able to significantly reduce glaucoma medication dependence by the fourth year. Indeed, 4 years postoperatively, 39% of the eyes required no medication, compared with none at baseline, and 72.2% were using one medication or less (

No serious complications were documented throughout the duration of the study, except for a case of limited descemetolysis near the limbus, which resolved spontaneously within 2 months. We surmise this was due to slow withdrawal of the catheter resulting in local over-delivery of OVD in the canal and subsequent temporary detachment of the Descemet membrane. Overall, our results suggest that ab-interno canaloplasty is not only effective but also a safe surgical procedure.

In 2022 we plan to start a prospective, non-randomised, multicentre study across four investigational sites in Europe, to assess the efficacy, safety and quality of life outcomes of canaloplasty combined with phacoemulsification and performed via an ab-interno approach using the new-generation iTrackAdvance, which has reengineered the previous microcatheter via a handheld injector design. This multicentre study, called CATALYST, will be performed over a 12-month period and will enrol up to 50 patients with mild-to-moderate uncontrolled OAG.

To sum up, in my experience, ab-interno canaloplasty offers significant versatility in real-world clinical practice and presents a useful tool in the glaucoma toolkit of comprehensive ophthalmologists and cataract surgeons, who typically see earlier-stage patients than their glaucoma surgeon peers. However, these encouraging results do not currently suggest that the technique can replace traditional glaucoma surgery or ab-externo canaloplasty, which we still use in our practice for more advanced glaucoma cases.

Ab-interno canaloplasty is effective in cases of controlled glaucoma, for patients who are intolerant or non-compliant to anti-glaucoma medications and thus have the treatment goal of reducing the number of medications required while maintaining IOP within target range, and possibly delaying the requirement for more invasive surgery and its subsequent increased risks and post-surgical complications.

Prof. Körber currently works at Augencentrum Koeln and at the Clinica Oculistica, University-Hospital of Padova, Italy. His areas of interest and expertise are cataract and glaucoma, with a special interest in canaloplasty. He has no financial or proprietary interest in any material or method mentioned but is the principal investigator for the Catalyst clinical study, which uses the product mentioned.

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9. Gallardo MJ, Supnet RA, Ahmed IIK. Viscodilation of Schlemm’s canal for the reduction of IOP via an ab-interno approach. 

10. Kazerounian S, Zimbelmann M, Lörtscher M, et al. Canaloplasty ab interno (AbiC) – 2-year-results of a novel minimally invasive glaucoma surgery (MIGS) technique. 

11. Koerber NJ, Ondrejka S. 4-Year efficacy and safety of iTrack ab-interno canaloplasty as a standalone procedure and combined with cataract surgery in open-angle glaucoma. 

12.Gallardo MJ. 24-month efficacy of viscodilation of Schlemm’s canal and the distal outflow system with iTrack ab-interno canaloplasty for the treatment of primary open-angle glaucoma. 

With minimally invasive surgery procedures becoming increasingly popular in glaucoma management, canaloplasty using an ab-interno surgical technique offers enhanced natural aqueous outflow in open-angle glaucoma.

A new treatment paradigm with ab-interno canaloplasty for POAG

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

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

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

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

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

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

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

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

Note: This transcript has been lightly edited for clarity.

Videos

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

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

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

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

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

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

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

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

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

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

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

Advancing IOL technology for treatment of presbyopia

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Making strides in ophthalmology with modern gene therapy techniques

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

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

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

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

Advancing IOL technology for treatment of presbyopia

Weekly review in ophthalmology: 14 May - 20 May