Data-Driven Management of Vitreoretinal Disease: Takeaways From AAO 2022

The 2022 American Academy of Ophthalmology (AAO) Annual Meeting, held September 30 to October 3 in Chicago, featured podium presentations on practice-changing treatments and robust debates on current controversies across a variety of ophthalmic subspecialties.
 
Jerry Sebag, MD, FACS, FRCOphth, FARVO, who attended the meeting, shares his key takeaways on updates in vitreoretinal care, discussing treatment paradigm shifts and controversial issues in patient management. Dr Sebag is a senior research scientist at the Doheny Eye Institute, UCLA, Los Angeles, California; professor of clinical ophthalmology at the Stein Eye Institute, Geffen School of Medicine, UCLA; and founding director at VMR Institute for Vitreous Macula Retina, Huntington Beach, California.

At AAO this year, your work on limited vitrectomy for treatment of vision degrading myodesopsia (VDM) — clinically significant vitreous floaters that reduce contrast sensitivity and impact visual function^1-3 — was featured during a pro/con debate with Dr Michael Cohen. Your position was that limited vitrectomy is a safe and effective way to cure patients with floaters who experience degradation in visual function, while Dr Cohen argued that the risks associated with vitrectomy are too great given that floaters often have no negative impact on visual acuity. Can you outline your position and explain why treatment of vitreous floaters continues to be controversial?

We have ignored our patients’ pleas for understanding, care, and cure of their vitreous floaters because until recently, we have not truly understood what is going on. More importantly, we have not had a way to measure the problem. For years, we were acting as psychiatrists, doing a personality profile to determine if the person in front of us was really afflicted or if they were just overreacting to a condition that many of us live with. Typically, we defaulted to an exam to reassure the patient that they do not have a problem with their retina; then we dismissed them, literally and figuratively. However, this approach was not satisfactory to patients. They wanted improved vision and a better quality of life.
 
Once I forced myself to analyze, measure, and understand the problem, everything changed. We were able to develop ways to assess vitreous structure with quantitative ultrasound and evaluate the effect on vision by measuring contrast sensitivity.

Visual acuity assessment is not very informative. Patients can have normal visual acuity but may still not be happy because they have contrast sensitivity degradation. Once we started measuring this, we could evaluate patients, compare their condition to that of hundreds of other individuals, and classify their degradation as mild, moderate, or severe. Patients with mild degradation can be reassured that they do not need treatment because their numbers serve to explain their status and why they are not candidates for surgery. Similarly, recommending surgery for patients became much easier because the ultrasound provided proof of vitreous densities that were substantially impacting their vision.
 
Not all floaters are the same, and I am not advocating surgery in all cases. I am advocating for an intelligent, objective, quantitative patient-evaluation approach to determine whether a given patient’s disease is mild, moderate, or severe. I then discuss the pros and cons of available therapies. The first step in making the paradigm shift is to realize that some people with vitreous floaters actually have a disease.

What do we know about the safety and efficacy of limited vitrectomy for treatment of vitreous floaters? 

We published a case series in the AAO journal Ophthalmology Retina detailing limited vitrectomy with 25-gauge instruments in 145 patients with bothersome floaters in 1 or both eyes.¹ Compared with 70 age-matched controls without floaters, the 145 patients with bothersome floaters had an average degradation in contrast sensitivity of 91.3%. Within 1 week of limited vitrectomy, every case was normal, and the contrast sensitivity remained normal for months and, in some cases, years thereafter. In terms of complications, in a series of 195 cases followed for an average of 32 months, with 51 cases followed for more than 4 years, there was no evidence of endophthalmitis or glaucoma. Vitreous hemorrhage occurred in 2 cases (1%) and cleared spontaneously. Retinal tears occurred in 3 cases (1.5%), and retinal detachments occurred in 3 cases (1.5%). All were identified and treated successfully. Three patients lost vision (1.5%); 2 of these cases were due to central retinal artery occlusion in older individuals with systemic hypertension, and 1 case was due to optic neuropathy. Cataract surgery was performed in only about 17% of cases, an average of 13 months after the limited vitrectomy. The average age of these patients was 64 years, and no patient younger than 53 years required cataract surgery.

What will it take for the paradigm shift that you speak of to occur?

Patients are going to drive this because they clamor for a better quality of life. There is no question that some people are significantly afflicted by vitreous floaters. I have seen case after case of high-powered individuals with better things to do than come to my office for an evaluation. They come in for a reason. Just because we have not been able to understand the reason until recently does not mean it does not exist. These people are miserable, and it is our job to identify those who are truly afflicted and cure them. 

When you determine a patient has VDM that is harming their visual function, how do you counsel the patient about limited vitrectomy?

I find it very useful to share the ultrasound results because they enable patients to see what is going on inside their eyes. That is a significant moment because often clinicians have told them they are fine, but they still believe something is not quite “right” with their vision. In our initial conversations, I always ask patients to try to cope with the problem. I show them a short film about limited vitrectomy. Then I discuss risks and possible complications. I tell patients that 3 people treated at my center have lost vision after limited vitrectomy and wish they had never undergone the procedure. We have to be transparent and share that.
 
We provide patients with all the information they need, and then we ask them to digest it, think about the implications, and try to cope further. There is a mechanism of neuroadaptation that can be beneficial, and I ask patients to try allowing that to happen. Surgery can be life-altering, but it needs to be done cautiously and deliberately based on quantitative objective measurements. I never operate on someone with normal contrast sensitivity and minimal vitreous opacification. Those are my personal criteria for whether or not a patient qualifies for the diagnosis of VDM and is a candidate for surgery.

The STAR trial (ClinicalTrials.gov Identifier: NCT02243878) compared visual outcomes in patients with visual loss from submacular hemorrhage secondary to neovascular age-related macular degeneration (nAMD) treated with surgery (vitrectomy with tissue plasminogen activator [tPA], gas tamponade, and treatment with a vascular endothelial growth factor [VEGF] inhibitor) vs pneumatic displacement with intravitreal injections of gas, tPA, and a VEGF inhibitor.⁴ Patients were followed for 6 months, with a primary endpoint of visual acuity change from enrollment to month 3. There was good visual acuity gain in both groups, but vitrectomy was not superior to intravitreal injection. What are your impressions of this study?

I have performed this surgery on multiple occasions. Some people recover a significant degree of vision, almost to 20/20. Once the accumulated blood has been reabsorbed, the degree of vision improvement will be determined by the underlying pathology. Patients with subfoveal pathology will not have good vision after the procedure, but those with extrafoveal pathology will have better vision. The problem is case selection. How can we determine prior to initiating treatment who will do better with surgery vs nonsurgical approaches? The difficulty in making that assessment is that the blood is blocking our view. We have to get more creative about how we use preoperative evaluation to decide whether surgery or another form of therapy is more appropriate for a specific patient.
 
It is not an emergency when a patient has a large submacular hematoma. There are several weeks of lead time before you intervene. You can give the patient a couple of injections and see if the blood clears, for example. I do not think waiting several weeks will make much of a difference. Surgery, on the other hand, is a big deal, and you do not want to put a patient through that unless there are real indications of benefit.

The 24-month data from DERBY and OAKS (ClinicalTrials.gov Identifiers: NCT03525600 and NCT03525613) — two phase 3 studies comparing efficacy and safety of monthly or every-other-month intravitreal pegcetacoplan vs sham injections in geographic atrophy secondary to age-related macular degeneration (AMD) — were also presented during AAO.^5,6 Dr Rishi P. Singh reported that patients treated with pegcetacoplan showed clinically meaningful reductions in geographic atrophy lesion growth at 24 months, with an increased treatment effect seen between months 18 and 24. Meaningful reductions in geographic atrophy lesion growth were demonstrated in both the nonsubfoveal and subfoveal subgroups. However, there were no clinically significant differences in visual function.⁵ Safety data reported by Dr David S. Boyer indicated that pegcetacoplan was well tolerated, with a safety profile generally consistent with that of other intravitreal agents. While the majority of cases of intraocular inflammation were mild, there were some cases of new-onset exudative AMD.⁶ What are your impressions of these data?

It is interesting that these studies were designed not to improve vision, but rather to arrest the progression of geographic atrophy. That is exciting because we have several ways to treat nAMD but no strategies to treat dry AMD. It would be very helpful to have a management plan to offer patients instead of just watching them lose vision. Nevertheless, intravitreal pegcetacoplan represents an important therapeutic option, and I look forward to offering it to at-risk patients. Patients with atrophy close to the foveal center would be very good candidates for this therapy. I do not know why anyone expected vision to improve in a patient with subfoveal atrophy, which simply cannot be reversed. I do not worry too much about the vision aspects.

Pegcetacoplan is currently under review by the US Food and Drug Administration (FDA) for ophthalmic use. If approved, it could become the first treatment for geographic atrophy. Would you care to speculate on the odds of its approval?

In its review process for ophthalmic therapies, the FDA historically has emphasized visual acuity, so the lack of vision improvement in DERBY might interfere with approval of pegcetacoplan. On the other hand, it is encouraging that the FDA accepted the trial design, with its primary endpoint of reducing geographic atrophy lesion growth.
 
It is always difficult to be the first drug of its kind. The DERBY and OAKS studies showed that geographic atrophy can be arrested, but patients were only studied for 2 years, a relatively short period of time. It would be very interesting to see what happens in years 3 to 6 because at that point, we might be able to better discern the true clinical benefit of treatment. The GALE extension study (ClinicalTrials.gov Identifier: NCT04770545) will provide longer-term data through 5 years for both monthly and every-other-month dosing of pegcetacoplan. However, we may not garner truly meaningful information about the value of this agent until it is approved and we gain real-world experience with its use.

The 2-year results from several phase 3 trials — TENAYA (ClinicalTrials.gov Identifier: NCT03823287), LUCERNE (ClinicalTrials.gov Identifier: NCT03823300) YOSEMITE (ClinicalTrials.gov Identifier: NCT03622580), and RHINE (ClinicalTrials.gov Identifier: NCT03622593) — were also presented at the AAO meeting.^7,8 TENAYA and LUCERNE assessed the efficacy, safety, and durability of faricimab, a bispecific angiopoietin-2 (Ang2)/VEGF-A inhibitor, compared with aflibercept in patients with nAMD,⁷ whereas YOSEMITE and RHINE assessed faricimab vs aflibercept in diabetic macular edema (DME).⁸ Individualized dosing of faricimab up to 16 weeks was safe and effective in patients with nAMD⁷ and DME,⁸ achieving vision stability and tight anatomic control. It was also durable, with approximately 45% and 60% of patients with nAMD and DME, respectively, experiencing vision gains with every-16-week dosing. No cases of retinal vasculitis or occlusive retinal vasculitis were reported in either pooled analyses. What do you take away from these trials?

The use of faricimab in this setting is a novel approach and the first time we have combined regimens with anti-VEGF and Ang2 effects. The data look very good, and faricimab seems to be superior to aflibercept. Faricimab also appears to be effective when administered once every 16 weeks. To restate the importance of these findings, they represent an innovative approach for 3 reasons: First is the fact that faricimab is active against 2 different signaling pathways. Second, treatment with faricimab is superior to the current standard of care. Third, it can be administered less frequently. All of these features benefit patients.

Should faricimab be a first-line agent in patients with nAMD and DME?

If a patient has been receiving a treatment that is working, there will be reluctance to make any changes. I do not think many patients will switch to faricimab unless they are really bothered by the injection burden. Those who are not doing well on their current anti-VEGF therapy will clearly switch to faricimab based on the results of these studies. In the case of treatment-naive patients, we will need to discuss options, like everything else. Faricimab will be part of that conversation, and it is up to the patient to decide whether or not to try a drug that has not been used for a long time in clinical practice. That will likely change with time, as more efficacy and safety data on faricimab are reported. Until then, some patients will prefer to wait and see how things go with other therapies before opting for treatment with faricimab. That said, there are always people who want the “latest and greatest” therapeutic options and will say, “Sure, let’s try the new agent.” It all comes down to discussing available options with patients and tailoring care based on an individual patient’s personal preferences and specific ophthalmic conditions.

This Q&A was edited for clarity and length.

References

1. Sebag J, Yee KMP, Nguyen JH, Nguyen-Cuu J. Long-term safety and efficacy of limited vitrectomy for vision degrading vitreopathy resulting from vitreous floaters. Ophthalmol Retina. 2018;2(9):881-887. doi:10.1016/j.oret.2018.03.011
 
2. Sebag J. Vitreous and vision degrading myodesopsia. Prog Retin Eye Res. 2020;79:100847. doi:10.1016/j.preteyeres.2020.100847
 
3. Sebag J. Vitrectomy for vision degrading myodesopsia. Ophthalmol Retina. 2021;5(1):1-3. doi:10.1016/j.oret.2020.08.013
 
4. Creuzot-Garcher C, Delyfer MN, Souied EH, et al. Surgery, tissue plasminogen activator, and antiangiogenic agents to treat submacular hemorrhage secondary to nAMD: results of a randomized controlled trial, the STAR study. Paper presented at: American Academy of Ophthalmology (AAO) 2022 Annual Meeting; September 30-October 3, 2022; Chicago, IL. PA026.
 
5. Singh RP, Boyer DS, Lad EG, et al. Efficacy of intravitreal pegcetacoplan in GA: 24-month results from the phase 3 OAKS and DERBY trials. Paper presented at: American Academy of Ophthalmology (AAO) 2022 Annual Meeting; September 30-October 3, 2022; Chicago, IL. PA024.
 
6. Boyer DS, Singh RP, Lad EG, et al. Safety of intravitreal pegcetacoplan in GA: 24-month results from the phase 3 OAKS and DERBY trials. Paper presented at: American Academy of Ophthalmology (AAO) 2022 Annual Meeting; September 30-October 3, 2022; Chicago, IL. PA069.
 
7. Singh RP, Khanani AM, Demetriades AM, et al. Faricimab in nAMD: year 2 results from the phase 3 TENAYA and LUCERNE trials. Paper presented at: American Academy of Ophthalmology (AAO) 2022 Annual Meeting; September 30-October 3, 2022; Chicago, IL. PA047.
 
8. Baumal CR, Wells III JA, Danzig CJ, et al. Efficacy, durability, and safety of faricimab in DME: two-year results from YOSEMITE and RHINE. Paper presented at: American Academy of Ophthalmology (AAO) 2022 Annual Meeting; September 30-October 3, 2022; Chicago, IL. PA023.

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