
Theresa Heah, MD, provides an update on AsclepiX’s AXT107, which is derived from a cryptic peptide within collagen IV that works by activating naturally existing, homeostatic mechanisms of angiogenesis, during the virtual 2020 American Society of Retina Specialists (ASRS) annual meeting.

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ASRS

Theresa Heah, MD, provides an update on AsclepiX’s AXT107, which is derived from a cryptic peptide within collagen IV that works by activating naturally existing, homeostatic mechanisms of angiogenesis.

AsclepiX lead candidate holds potential for wet AMD, DME, RVO (ASRS 2020)

This article was reviewed by Sunita Radhakrishnan, MD

Assessing the angle is important for glaucoma management. It can identify various mechanisms of IOP elevation, such as pigment dispersion and angle recession, and is critical for the diagnosis and staging of primary angle closure. It is also important in treating glaucoma.

“The angle must be visualized in order to perform laser trabeculoplasty, for example, at least when using the devices that are currently available,” said Sunita Radhakrishnan, MD, research director, Glaucoma Research and Education Group at the Glaucoma Center of San Francisco. “A new technology is in the pipeline that enables transscleral laser trabeculoplasty but for now, visualization of the angle is necessary to deliver laser energy to the trabecular meshwork. There are several minimally invasive glaucoma surgeries that also require angle visualization.”

In a clinic setting, physicians often use the Van Herick method, which can be performed rapidly, as a substitute for indirectly assessing the width of the angle. However, she questioned if this is the best route to take.

 that evaluated the diagnostic capability of the Van Herick test when performed by observers with different levels of expertise who may all be involved in angle assessment. The study found that the sensitivity of the Van Herick test to detect gonioscopic angle closure ranged from 58% among technicians to 79% among residents.

“This is low sensitivity when screening patients for angle closure,” she noted.

 also addressed risk factors associated with misdiagnosis when using the Van Herick test to detect angle closure.

“The risk of misdiagnosis was found to be higher in patients with more severe angle closure, that is, those with primary angle-closure disease, instead of the primary angle-closure suspects, which is concerning,” Radhakrishnan said.

Indirect assessment using the Van Herick test cannot only miss angle closure but it also cannot detect angle pathology that could be present in patients with a deep anterior chamber and no obvious glaucoma risk factors. A classic example, Radhakrishnan said, is angle recession in a patient with an old and forgotten ocular injury.

These studies underscore the importance of directly viewing the angle structures with gonioscopy. This test provides a 360

“The observer can perform indentation in angle closure and identify peripheral anterior synechiae as well as plateau configuration. We can also detect various other causes of elevated pressure, such as pigment dispersion, neovascularization, and recession,” Radhakrishnan said.

In her glaucoma practice, Radhakrishnan performs gonioscopy on every patient. However, there is an argument that gonioscopy should be performed even in patients who do not have known risk factors for glaucoma.

“This is a strategy to opportunistically screen for angle closure,” she pointed out, in light of the high visual morbidity of primary angle-closure glaucoma and the fact that population-based screening is not feasible for this disease.

It is also important to periodically repeat gonioscopy in patients with phakic IOLs because even those in whom the angle is open at baseline can ultimately develop angle closure as a result of lens thickening over time.

When performing gonioscopy, the main landmark and usually the most easily recognized one is the scleral spur, which lies between the pigmented trabecular meshwork and pigmented ciliary body.

Radhakrishnan said when she performs gonioscopy, she first locates the scleral spur. If it is not visible in the first quadrant examined, then she looks in another quadrant in which the trabecular meshwork pigmentation may be more prominent. If the scleral spur still is not visible, Radhakrishnan suggests tilting the goniolens slightly; if the spur remains undetectable, then she performs indentation gonioscopy to differentiate appositional from synechial angle closure.

Very pale trabecular meshwork may increase the difficulty in visualizing the scleral spur. In such patients, she recommends starting at Schwalbe’s line (which can be identified with the corneal wedge technique) and working backward from there. Schwalbe’s line is often pigmented, especially in the inferior quadrant and can be mistaken for the trabecular meshwork, so care should be taken in interpreting the angle status to avoid misclassifying a closed angle as open.

When gonioscopy is performed in the operating room, different steps are necessary from those performed in the clinic.

Radhakrishnan referred residents, fellows, and novice surgeons to the American Academy of Ophthalmology website for tips on gonioscopy in the operating room (

https://www.aao.org/clinical-video/intraoperative-gonioscopy).

“The main consideration is that the microscope illumination changes from coaxial for cataract surgery to being directed along the iris plane and onto the angle,” she explained. “To achieve this, the microscope is tilted about 30

toward you and the patient’s head is turned about 30

away from you. This increases the working distance by several inches, which takes a little time to become accustomed to.”

Another difference from the examination performed in the clinic is that a surgical (direct) goniolens is used in contrast to the indirect lens in clinic. A coupling agent is used on the cornea as well as adequate viscoelastic in the anterior chamber. She prefers Healon GV (Johnson & Johnson Vision) and noted that the product name is now Healon GV Pro to indicate a change in the formulation; the new formulation was recalled by the FDA and Healon GV has not been available for several months. Some recommendations that have been suggested for replacing Healon GV are Healon 5 and ProVisc (Alcon Laboratories), Radhakrishnan recounted.

Despite being the best way to directly evaluate the angle, gonioscopy does have limitations. “It is a subjective procedure, and it needs a slit lamp as well as a highly trained observer. In addition, there are potential sources of error regarding detection of angle closure because of the use of illumination and the contact with the eye,” Radhakrishnan said and noted that angle imaging is an alternative that overcomes some of the limitations of gonioscopy.

Cross-sectional imaging of the angle can be performed with optical coherence tomography (OCT) and ultrasound biomicroscopy (UBM). The former is a noncontact technology that facilitates assessment in the dark and the entire anterior chamber is visualized in 1 scan. The disadvantage is that visualization of structures behind the iris is not possible.

OCT provides several options to image the angle. The dedicated anterior-segment OCT (Visante OCT, Carl Zeiss Meditec) is best for visualizing the angle recess, but this machine is not widely available. Angle imaging can also be done with a retinal OCT device, but the scleral penetration is not as good as with the Visante. Radhakrishnan uses a Visante OCT in her practice and also has access to Cirrus OCT (Carl Zeiss Meditec) with an anterior-segment external lens kit that can be attached to the machine to obtain images of the angle.

UBM provides excellent visualization of the angle structures both in front of and behind the iris. However, traditional UBM with an immersion bath is time consuming, and a highly trained ultrasound technician is needed.

With both technologies, as with gonioscopy, the scleral spur is the key landmark to locate.

Radhakrishnan typically uses imaging as an adjunct to gonioscopy to identify primary versus secondary angle-closure mechanisms. However, imaging can also be a substitute for gonioscopy for patients who cannot tolerate a contact procedure or if corneal pathology does not permit visualization of the angle by gonioscopy.

She also relies on imaging to educate patients about their disease and to explain why laser or surgery might be recommended in certain situations.

“OCT is my first-line imaging device because it is easy to use and comfortable for patients,” Radhakrishnan said.

UBM is reserved for viewing structures posterior to the iris and for evaluating plateau configuration.

“I would like to encourage clinicians to perform gonioscopy more often,” she concluded. “Know the landmarks and use imaging technologies as adjuncts to gonioscopy. Remember that gonioscopy performed in the operating room is different from that in clinic.”

Johnson TV, Ramulu PY, Quigley HA, Singman EL. Low sensitivity of the Van Herick method for detecting gonioscopic angle closure independent of observer expertise. 

 2018;195:63-71. doi: 10.1016/j.ajo.2018.07.026

Atalie C. Thompson, Daniel M. Vu, Lisa A. Cowan, Sanjay Asrani. Risk factors associated with missed diagnoses of narrow angles by the Van Herick technique. 

 2018;1(2);108-114. doi.org/10.1016/j.ogla.2018.08.002

Radhakrishnan has no financial interests to disclose.

Articles

GLAUCOMA 360

How gonioscopy can offer ophthalmologists an option in treating patients with glaucoma 

Assessing the angle: Getting back to basics


During the virtual 2020 ASRS annual meeting, Josh Anderson speaks with 

' Sheryl Stevenson on the highlights from Alcon, including new data on the performance benefits of the Hypervit dual blade 20,000 cpm probe and the launch of the NGENUITY 1.4 upgrade.

ASRS 2020: Josh Anderson speaks on the highlights from Alcon, including new data on the performance benefits of the Hypervit dual blade 20,000 cpm probe and the launch of the NGENUITY 1.4 upgrade.

Alcon showcases latest retina innovations, data (ASRS 2020)


Derek Kunimoto, MD, JD, focuses on Aviceda's technology, which will aim to target various immune system responses that contribute to pathology associated with dry AMD, in an interview with Sheryl Stevenson, 

® group editorial director, during the virtual 2020 American Society of Glaucoma Specialists (ASRS) annual meeting.

Derek Kunimoto, MD, JD, focuses on Aviceda's technology, which will aim to target various immune system responses that contribute to pathology associated with dry AMD. 

What Aviceda’s lead candidate AVD-104 may mean for dry AMD (ASRS 2020)

Dilraj Grewal, MD, associate professor of ophthalmology at Duke Eye Center/ director of grading at the Duke Reading Center, speaks with Ophthalmology Times®' David Hutton on his presentation "Evaluating the True 3-Year Recurrence Rate in Non-infectious Posterior Segment Uveitis Following an Injectable Fluocinolone Acetonide Insert (FAi)," during the Inflammatory and Infectious Diseases Symposium of the virtual 2020 American Society of Retina Specialists (ASRS) meeting.

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Dilraj Grewal, MD, associate professor of ophthalmology at Duke Eye Center/ director of grading at the Duke Reading Center, speaks on his presentation "Evaluating the True 3-Year Recurrence Rate in Non-infectious Posterior Segment Uveitis Following an Injectable Fluocinolone Acetonide Insert," during the virtual 2020 ASRS meeting.

Evaluating 3-year-recurrence rate in non-infectious posterior segment veitis post-FAi

Great inventions start with an idea, but only a small fraction moves past that phase through increasingly complicated, work-intensive developmental stages.

Leaders in the field guided investigators through the route their ideas must take to reach fruition. Malik Kahook, MD, professor of ophthalmology, University of Colorado, and Adrienne Graves, PhD, co-founder and co-chair of Glaucoma 360, moderated this discussion.

Considerations when attempting to “grow” an idea into a viable product are the risks involved—emotional, financial, and reputational. 

“These factors seem theoretical until they become real, as people are judging if your approach is sound,” said John Berdahl, MD, who is in private practice at Vance Thompson Vision, Sioux Falls, South Dakota.

The next step is determining if the idea is good (i.e., interesting and important) and can satisfy a marketable need. This stage must be coupled with a high level of motivation to pursue that idea and accomplish the level of work needed to bring it to realization. Finding mentors, performing proof-of-concept science, and being honest with all involved individuals about whether the idea will take off are also mandatory steps.

Importantly, the idea must be legally protected with a patent. Entrepreneurs must protect a space to prevent others from developing something similar.

Berdahl also offered a practical tip: develop the intellectual property before starting the company and then license the property to the company for a royalty. Physicians must also learn about how venture deals are structured, executing a business, and staying focused.

Forge pathways through the FDA and reimbursements. Berdahl advised engaging early with the FDA (which provides useful information about achieving approval) and payers to determine what can be reimbursed. Team building is the final and perhaps most vulnerable step to assemble a group of people who are dedicated to making the idea a reality.

“The next step after developing a medical prototype is raising capital,” said Reza Zadno, PhD, CEO of Glaukos. This is easier said than done for novice entrepreneurs. Raising capital also presents questions about who benefits from the product, the patient with better outcomes, the provider with shorter surgical times and better economics, or the payers?

“The most exciting projects for potential investors are those that satisfy everyone—generally high-risk, high-benefit projects,” Zando said. “However, they are also more difficult. A clear path is needed because the patients, provider, payer, and the costs of goods are generally unclear.”

The parties involved evoke myriad questions. For regulators: the FDA history with similar products, regulatory pathways, and is the product paid for by the patient or reimbursed? Have investors lost money with similar products? Are providers interested in new technology?

In some cases, a prototype is not always necessary.

Experience is key to selling the project—with an experienced founder who can define a clear pathway and risk for investors and with experienced capitalists who will ultimately invest in the project.

Every step in the process of developing a new treatment involves establishing and ensuring continuous funding, according to Eugene de Juan Jr, MD, vice chairman of ForSight Labs.

The key to keeping venture capitalists interested in a project is by reducing risk, he noted.

“Entrepreneurs must design, think, [create a] prototype, and test continuously to show that whatever they have is working,” he said.

To ensure the money flow, developers must ask if the product solves a clinical need.

“Human experience is what drives the needle, rather than in vitro and animal models,” de Juan emphasized.

Another consideration is the form. He continued, “Is it attractive? Do patients, doctors, and payers like it?”

Some thoughts for ophthalmologists to live by: Costs increase immensely with decreasing risk as the clinical programs progress. The risks of not progressing through the stage of development increase with each step; failing early can be absorbed by large, not small, companies.

There is a 50% chance of a drug getting through a phase 2 trial. Overall, the success rate from a drug to a clinical approved outcome is about 1 in 100.

The key to not failing late is not to start if failure is in the cards.

The Center for Drug Evaluation and Research ensures that safe and effective products are available for the American public. 

Our goal is to try to approve products that are safe and efficacious,” said Wiley Chambers, MD, deputy director of the Division of Transplant and Ophthalmology Products in the Center for Drug Evaluation and Research of the FDA.

When a product is involved in the approval process, Chambers advises applicants not to do something that they believe the FDA wants them to do when the company and the FDA do not think it is necessary.

The product being tested must have a vehicle that is an acceptable control.

The noninferiority margin is based on multiple previous drug trials. The 95% confidence interval that shows the test product produces the same result as the other products most of the time within 1 mm Hg indicates that within that margin, the drugs are the same, he explained.

In the United States, the generic solutions of timolol, bimatoprost, latanoprost, and travoprost have the same active and inactive ingredients in the same concentrations and these can be used in clinical trials.

The FDA requires comparisons of the peak and trough times of the drug tested and the control, that the measurements are done 2 weeks after treatment onset to be certain of the drug’s effect, and measurements are performed at 12 weeks because drugs that work then continue to be efficacious after that time. The FDA also wants drugs to be studied bilaterally as long as the eyes are within 5 mm Hg. “There are reasons behind everything the FDA asks for,” he said. “If you don’t know the reason, please ask.”

If considering a start-up, Thomas A. Mitro, president and chief operating officer of Aerie Pharmaceuticals Inc., advised hiring the best, most experienced people, who are not necessarily the most affordable, to lead the company through start-up turmoil.

In line with that, he also advised that they be paid well and not in stock options, before another company scoops them up.

Virtual start-up companies (and departments within those companies)—although very attractive—are difficult to build and establish the company culture and repertoire among employees scattered across the United States and globally.

To combat the negative aspects of having a company with multiple sites worldwide, Aerie Pharmaceuticals brings all employees together at 1 location for an annual meeting. The company also encourages immediate decision making by employees.

“Quick start-ups are encouraged and in like manner, fail as quickly as possible. Long exits waste time and money,” Mitro said.

He advised companies not to fall prey to failures by other companies in the industry that are attempting similar start-ups.

Finally, Mitro advised building relationships, not enemies; other companies should be considered competitors who are treated with respect.

Researchers must weigh emotional, financial, and reputational considerations

Developing a new therapy: Where do we go from here?



The Port Delivery System (PDS) with ranibizumab ( (Lucentis, Genentech, Inc.) met the primary endpoint of the Archway Trial of equivalency and reduced treatment burden when compared with monthly ranibizumab injections, the gold standard, for treating neovascular age-related macular degeneration (AMD).

“Patients with neovascular AMD are often undertreated clinically, leading to suboptimal outcomes, according to Peter Campochiaro, MD, presenting during the American Society of Retina Specialists 2020 Virtual Annual Meeting. “More durable treatments are needed, and the PDS with ranibizumab is an innovation solution for these patients.”

The PDS, an investigational drug delivery system, provides continuous delivery of a customized formulation of ranibizumab; it is a permanent intraocular reservoir that can be refilled during an in-office procedure. 

Ranibizumab is slowly released into the vitreous cavity following implantation at the pars plana.

Campochiaro recounted that the phase 2 Ladder trial of the PDS (100 mg/mL) for neovascular AMD found that the visual and anatomic outcomes were comparable to those obtained with monthly ranibizumab 0.5-mg injections. 

The PDS did not need to be refilled for about 24 weeks or longer in 80% of patients. These favorable results supported the device’s evaluation in the Archway phase 3 trial.

The ongoing trial includes patients (n = 415) with neovascular AMD who had been responsive to any anti-vascular endothelial growth factor therapy. 

The patients were randomized 3:2 to the PDS with ranibizumab (100 mg/mL) doses every 24 weeks (248 patients) or monthly intravitreal injections of ranibizumab 0.5 mg (167 patients), with the goal of evaluating the noninferiority and equivalency of the PDS compared with the injections.

The primary endpoint was the change in the best-corrected visual acuity (BCVA) compared with baseline averaged over weeks 36 and 40. If disease activity became apparent in the PDS group during the study course, patients could receive supplemental injections of ranibizumab.

The baseline BCVA was 20/32 in both groups following a mean of 5 anti-VEGF injections before baseline. The study had a 98% retention rate at the primary analysis.

Campochiaro reported that the Archway Study met the primary endpoint, i.e., the PDS with every-24-week dosing was noninferior and equivalent to monthly ranibizumab. 

“Compared with the gain in 0.5 letter in the monthly injection arm, the gain of 0.2 letter in the PDS arm was noninferior and equivalent to the protocol-specified margin for each of 4.5 letter,” he commented.

A transient reduction in the BCVA was seen in the PDS arm that was related to the implantation procedure. The BCVA returned to the baseline value by week 12.

“The excellent baseline BCVA from previous treatment was well maintained in each study arm,” he said. In line with this, the normal baseline center point thickness was maintained through week 40 in the PDS arm, similar to the injection arm.

The vast majority of patients in the PDS group (98%) did not require supplemental treatment during the first refill-exchange interval.

“To week 40, the total number of treatments, i.e., implantation, refills, or supplemental injections, was 2 in the PDS arm compared with 10.7 injections in the monthly ranibizumab arm,” he said.

The device implant and refill-exchange procedures were generally well tolerated, but there were some adverse events of special interest. 

In the PDS arm, the adverse event that occurred most often was a nonserious conjunctival bleb in 6.5% of patients; vitreous hemorrhages occurred in 5.2% and resolved spontaneously; no traumatic cataracts developed; conjunctival retraction/erosion occurred in 4.4%. 

Four cases (1.4%) of endophthalmitis developed that were related to the conjunctival retraction; in 1 case the visual loss was irreversible and in 3 cases the vision returned to the baseline level. Two retinal detachments occurred that required surgery. 

The device dislocated in 1 case into the vitreous cavity during a refill-exchange procedure; the device was removed and the vision returned to baseline.

The major take-home points are the following. The trial showed that the PDS met the primary endpoint of equivalency and reduced treatment burden compared with monthly ranibizumab. 

The combination of surgery, device, and drug was generally well tolerated with a favorable benefit/risk profile.

“Since ranibizumab was approved in 2006, new treatments have provided incremental benefits,” Campochiaro concluded. “The PDS is the first new treatment that provides a paradigm shift in the management of neovascular AMD.”


Dr. Campochiaro is on the advisory board of Genentech and is an investigator for and received grant support and honoraria from Genentech. He is lead author of this study, and professor of ophthalmology, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 

ASRS 2020 coverage: Peter Campochiaro, MD, detailed findings of phase 2 of the Ladder Trial and ongoing Archway Trial during the virtual 2020 American Society of Retina Specialists (ASRS) annual meeting.

PDS with ranibizumab signals paradigm shift in treatment of nAMD



The results of the Protocol T Extension Study to assess treatment of center-involved diabetic macular edema (DME) with anti-vascular endothelial growth factor (VEGF) therapy showed visual acuity (VA) declines over the 3-year period after the end of the Protocol T study.

While the final VA at the 5-year time point remained above that achieved at the end of the Protocol T study, the results emphasized the need for methods to maintain the initial VA increases achieved.

Dante Pieramici, MD, reported the results of the Protocol T Extension Study on behalf of the DRCR Retina Network during the virtual 2020 American Society of Retina Specialists (ASRS) meeting.

Protocol T was a 2-year multicenter clinical trial in which aflibercept (Eylea, Regeneron Pharmaceuticals), bevacizumab (Avastin, Genentech, Inc.) and ranibizumab (Lucentis, Genentech, Inc.) were compared for treating DME in 660 eyes in which the baseline VAs ranged from 20/32 to 20/320. 

All patients had center-involved DME and had received no or minimal treatment for the DME, Dr. Pieramici recounted.


In the extension study, the eligible patients were assessed during a 5-year visit, i.e., 3 year after the end of Protocol T. 

At the 5-year visit, the VA was measured, optical coherence tomography images and color photographs were obtained, and patients were examined.

“The primary objective of the extension study was to obtain additional information about the 3 years after the end of Protocol T to gain insight into the treatment course and follow up on the VA and DME in years 2 to 5. 

The main outcome was not to compare the treatments groups after 2 years because the patients had been managed at physician discretion during that time,” he said.

A total of 317 patients were eligible to participate in the extension study. Of these, 95% of the participants had undergone 1 or more retinal examinations (mean, about 14) since the end of Protocol T.

During the 2- to 5-year period, 70% of patients were treated 1 or more times for DME or diabetic retinopathy, most of which were anti-VEGF drugs (median number of injections, 4 in about 67% of patients); small percentages of patients were treated with corticosteroids, focal or grid laser, or panretinal photocoagulation, Dr. Pieramici reported.

About a third of patients did not receive additional VEGF injections during the period of the extension study, and about 10% received 20 or more injections during the evaluated time period.

“At the end of the extension study, the VA decreased to an average of +7.4 letters compared with the Protocol T increase of +12.2 letters in all treatment groups, for a mean decrease of about 1 line of VA, Pieramici said. “However, this level was still better than the baseline VA. When the effects of anti-VEGF treatments were analyzed, the same downward trajectory was seen for the 3 drugs.”

When the VA was analyzed according to the baseline VAs, the same pattern of results was seen. 

However, despite the VA decline over the 3-year period, almost 50% of the patients had 20/25 or better VA at the 5-year time point and 75% had 20/40 or better VA.

The mean central subfield thickness changed very little between years 2 and 5, -156 µ versus -154 µ, respectively. 

This also was the case when the groups were analyzed based on the original treatments. At 5 years, only about one-third of patients had some measurable DME.

Based on the results of the Protocol T Extension Study, the takeaway points were as follows:

 The patients received standard care after Protocol T concluded. That is, 95% of patients received retinal care and 68% had at least 1 injection of an anti-VEGF drug. On average, the patients maintained VA gains from baseline, but the mean VA decreased from years 2 to 5, and the central subfield thickness did not change significantly during those years.

 The results of the Protocol T Extension Study differed from previous studies of DME that reported sustained VA increases, as in the Protocol I study.

 Strategies are needed to improve the long-term VA outcomes in the clinical care of eyes with DME.

Dr. Pieramici is a consultant to and receives research funding from Genentech, Inc. and Regeneron Pharmaceuticals. He is in private practice in Santa Barbara, California. 

ASRS 2020 coverage: The results of the Protocol T Extension Study underscore the need for methods to improve long-term visual gains in eyes with diabetic macular edema, according to Dante Pieramici, MD,on behalf of the DRCR Retina Network.

Protocol T Extension Study shows long-term visual declines in DME eyes

Trabeculectomy and tube procedures are still needed, and minimally invasive glaucoma surgery (MIGS) has a permanent niche. 

Choosing the appropriate one to perform depends on the needs of the patient, not on those of the surgeons, according to Kuldev Singh, MD, MPH.

Most patients with mild to moderate, slowly progressive glaucoma do not need to undergo a trabeculectomy or tube procedure, explained Singh, a professor of ophthalmology and director of glaucoma at Stanford University in California.

“MIGS works nicely because the safety risk-to-benefit profile is very favorable for MIGS in those patients,” he said.

Trabeculectomy and tubes provide more benefit for those patients with advanced glaucoma who are losing vision, and these procedures will remain beneficial for a long time.

To underscore his point, Singh cited a large population study with several thousand patients in which Bal Chauhan, MD, and colleagues evaluated how rapidly glaucoma progressed over a 7-year period.

 They found that only about 2% to 3% of patients have rapid and catastrophic progression, he noted.

“Most of the other patients were part of a normally distributed curve around no change,” Singh recounted.

However, with aging, some patients in the later decades of life begin to deteriorate, despite having intraocular pressure (IOP) in the low teens.

“With the aging of the population, we are going to see many more patients with glaucoma that is worsening. [In the case of] these patients, their parents did fine ... in [their] 70s and 80s, but [they] will have trouble with glaucoma later in life,” he said.

Based on this, Singh foresees a virtual epidemic of older patients with severe glaucoma disease that requires very low IOP.

“The reason we have shied away from performing trabeculectomy and tubes in these patients is because of bleb maintenance. We must weigh the risks and benefits in individual patients to determine [whether] these procedures make sense,” Singh explained.

Regarding trabeculectomy and tube procedures, these are excellent for lowering IOP and the results of various studies bear that out. For example, in a randomized comparison clinical trial of 5-fluorouracil and mitomycin C for a first procedure conducted in the 1990s, slightly more than 50% of patients had IOPs under 12 mm Hg after 3 years.

The Tube versus Trabeculotomy (TVT) Study (NCT00306852) of eyes that had been previously operated on showed that both procedures provided low IOPs. The more recent TVT study showed that both procedures provide low IOPs, with trabeculectomy performing slightly better with IOPs around 10 mm Hg.

In addition, according to Singh, the PreserFlo MicroShunt (InnFocus), a highly anticipated device awaiting FDA approval, did well when compared with trabeculectomy.

Both had similar results in a randomized clinical trial, but trabeculectomy also provided IOPs in the 10 mm Hg range. 

“From an IOP standpoint, it is hard to do better than trabeculectomy, which also might be a little better than tubes,” he commented.

The results from another clinical study, conducted by Joseph Caprioli, MD, provided an interesting observation: When trabeculectomy lowers IOP a great deal, the visual fields improve.

“I see this in clinical practice in patients with a 10- or 15-point improvement in the visual field index when the IOP decreases from the low teens to 5 or 6 mm Hg,” Singh said.

The effect of trabeculectomy is titratable

Singh pointed out that when patients are losing vision despite IOPs in the 10- to 15-mm Hg range, surgeons may be afraid to perform trabeculectomies that might lower the IOPs into the single digits.

“Many older patients with severe glaucoma require an IOP of 6 mm Hg and not 12 mm Hg. I think we will continue to see more cases like this,” he said.

This paradigm shift seems to be occurring. Singh recounted how the Aegis Study, which served as the glaucoma bible for a long time, had surgeons believing that glaucoma ceased with no further progression at an average of 12 mm Hg.

“What seemed to be happening in that study was that a subset of patients with low IOP did slightly better than those with a slightly higher IOP,” he noted. “The concept of glaucoma stabilization is not great. Generally, glaucoma worsens, but in some cases, there is an improvement when the IOP is lowered a great deal.”

This aging of the population may be why MIGS might not replace trabeculectomies and tubes.

“When we have low IOP goals in advanced disease, we have proven success with trabeculectomies and tubes, and the former allows titration of the IOP to the desired level based on patient needs,” Singh said.

No one is certain whether the IOP decrease is maintained over time. “It may not last indefinitely, but in the 3- to 5-year period, I have seen patients with substantial improvement in visual function after trabeculectomy,” he said.

Singh believes that MIGS is not a passing fad.

“[It has] added so much to our armamentarium. So many patients benefit from MIGS,” he said.

The procedure started off as a microincisional surgery and evolved into a minimally invasive procedure. However, it is not the answer in every case.

Singh noted that although younger surgeons seem to prefer MIGS for a number of reasons, he advises them to keep the needs of the patient at the forefront. This is particularly so in cases where trabeculectomy, which is more labor intensive and has a lower reimbursement rate, may be a better option.

Regarding glaucoma surgery in the 2020s, Singh said ophthalmologists are seeing continuing growth of MIGS and that new and exciting devices are being developed. Many older patients with severe glaucoma need trabeculectomy.

“I believe a patient-focused approach will emerge,” he concluded. “The surgery is for the patient and not the surgeon. I also believe that 6 mm Hg will become the new 12 mm Hg, and as surgeons opt out of performing trabeculectomies, those surgeons who can perform the surgeon and get the consistently lower results, I can envision a premium channel developing for this traditional surgery that may ultimately provide higher reimbursement.” 

Chauhan BC, Malik R, Shuba LM, Rafuse PE, Nicolela MT, Artes PH. Rates of glaucomatous visual field change in a large clinical population. 

2014;55(7):4135-4143. doi:10.1167/iovs.14-14643

Caprioli J, de Leon JM, Azarbod P, et al. Trabeculectomy can improve long-term visual function in glaucoma. 

 2016;123(1):117-128. doi:10.1016/j.ophtha.2015.09.027

Trabeculectomy may offer better results with more severe glaucoma

Traditional glaucoma surgery in the era of MIGS procedures

), when tested at extended dosing intervals of every 16 weeks and every 12 weeks, provided sustained anatomic and visual outcomes comparable to those achieved with ranibizumab (Lucentis, 

The phase 2 Stairway Trial showed that the drug blocked angiopoietin 2 (Ang-2) and vascular endothelial growth factor (VEGF), both of which synergistically drive vascular instability, characterized by vascular leakage, neovascularization, and inflammation in retinal diseases such as age-related macular degeneration (AMD), according to Carl Danzig, MD, who presented results of the trial during the virtual 2020 American Society of Retina Specialists annual meeting.

Faricimab is the first bispecific antibody designed for intraocular use and can simultaneously bind and neutralize Ang-2 and VEGF-A. 

He explained that the bispecific antibody has 2 Fab arms in a specifically engineered Fc region: Anti-Ang-2 Fab stabilizes and protects vessels and anti-VEGF-A Fab inhibits vascular leakage and neovascularization.

The phase 2 multicenter, randomized, controlled clinical study evaluated the extended durability of faricimab for treating neovascular AMD. 

Specifically, the investigators assessed the effects of every-16-week flex doses or every-12-week doses of faricimab compared with monthly ranibizumab. All patients treated with faricimab first received 4 doses administered every 4 weeks through week 12 (loading dose) followed by a 12-week period with no treatment. 

At week 24, the disease activity was assessed, including measurement of the central subfield thickness and BCVA, presence of macular hemorrhages, and the investigators’ opinions. 

The primary efficacy objective was the change in the best-corrected visual acuity (BCVA) from baseline.

The patients randomized to the every-16-week flex dosing who had active disease at 24 weeks went on to every-12-week dosing. Those without active disease were eligible for every-16-week dosing.

“Overall, 65%, that is, 36 of 55 patients treated with faricimab were free of disease activity at week 24; 19 of 31 patients in the every-16-week flex group had no disease activity at week 24 and were treated at every-16-week intervals to week 52,” Danzig said. “All other patients were treated with every-12-week dosing.”

Measurements of the BCVA showed that the gains in vision achieved with the every-16-week flex dosing and every-12-week dosing were maintained at week 52 and were comparable to those seen with monthly ranibizumab (+11.42, +10.08, and +9.59 letters, respectively).

Improvements in BCVA, central subfield thickness, choroidal neovascularization lesion size, and area of leakage with faricimab dosed every-16-week flex and every 12 weeks were comparable to those achieved with monthly ranibizumab.

According to Danzig, the main take-home points of the study include Ang-2 and VEGF-A are key drivers of vascular instability characterized by vascular leakage, neovascularization, and inflammation. Faricimab is the first bispecific antibody designed to simultaneously inhibit Ang-2 and VEGF-A.

The Stairway trial showed that the initial BCVA gains were meaningful and fully maintained through week 52 with every-16-week flex and every-12-week dosing arms. 

No active disease was seen in 65% of all patients treated with faricimab 12 weeks after the last loading dose and were eligible for every-16-week dosing. Anatomic improvements were comparable between faricimab and ranibizumab.

According to Danzig, based on the Stairway trial results, 2 large phase 3 studies, Tenaya and Lucerne, are assessing the efficacy, safety, and durability of faricimab in patients with neovascular AMD. The drug is also under investigation in phase 3 clinical trials to treat diabetic macular edema.

Dr Danzig is a consultant to Genentech Inc. He is is in private practice at the Rand Eye Institute, Pompano Beach, Florida.

ASRS 2020 coverage: Carl Danzig, MD, presented results of phase 2 Stairway Trial during the virtual 2020 American Society of Retina Specialists (ASRS) annual meeting. Faricimab is a bispecific antibody that simultaneously inhibits angiopoietin-2 and vascular endothelial growth factor A.

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