Anti-Vascular Endothelial Growth Factor Treatment Strategies in Wet Age-Related Macular Degeneration

Ehsan Rahimy, MD, is a retina specialist and an adjunct faculty member at Stanford University in Palo Alto, California, where he helps train surgical retinal fellows. Dr Rahimy has extensive experience researching medical and surgical diseases of the retina. He has more than 100 peer-reviewed scientific publications and has contributed to over 150 abstracts presented at national and international ophthalmic meetings. 

What clinical features are assessed when monitoring response to anti-VEGF therapy in a patient with wet AMD? How closely is the reduction in retinal fluid monitored?

I am monitoring 3 clinical features at each visit: First is the patient’s objective anatomic response and our main surrogate for this is optical coherence tomography (OCT). Using OCT, we can reliably monitor the treatment response by assessing fluid status in the eye. We are looking for buildup of intraregional fluid and/or subretinal fluid, and recurrent hemorrhage. It is often necessary to complement the imaging with examination of the dilated retina because the patient may be experiencing a minor recurrent hemorrhage that cannot be readily appreciated using OCT alone.
 
Second, we look at the objective functional response related to visual acuity. This means assessing changes in the patient’s vision over time and on a visit-to-visit basis. There can be considerable variability in testing visual acuity in the clinic on a day-to-day basis, and real-world testing differs from the stringent vision testing protocols used in clinical trials. For example, acuity differences between visits can be related to factors other than a change in the patient’s disease process, including different examination lane conditions, variations in the workup performed by different technicians, or patient-specific factors such as patients having dry eyes during a particular visit or forgetting to bring their corrective lenses. Given the variability that we often deal with in the “real world,” I am evaluating patients for significant declines in visual acuity or complementary changes on imaging that indicate a clinically-meaningful change in vision. 
 
Last and most important is the patient’s subjective response. Sometimes OCT and visual acuity testing results may suggest stable disease, but patients are certain that they notice a difference in their vision in the last week before their next treatment dose, a period where the medication effect may have worn off and their disease is reactivating. Notably, while reading speed, contrast vision, color vision, and visual fields may all be depressed in AMD, those changes will not necessarily be evident from objective letter acuity testing.^1-3 

Anti-VEGF biosimilars are now being evaluated in clinical trials. How might the availability of anti-VEGF biosimilars affect the treatment landscape for patients with wet AMD?

This is going to be very interesting, given that ranibizumab-nuna and ranibizumab-eqrn have both been approved by the US Food and Drug Administration (FDA) and aflibercept biosimilars are in the pipeline. For possible answers to this question, we can look to case studies and clinical research from our colleagues in hematology, oncology, and rheumatology, who have had a longer period of time to evaluate the impact of biosimilars on their daily practice. One report noted that the cost of biosimilars are approximately 20% to 30% below the cost of the respective branded agent, and that may make a difference to payers.⁴ In the care of patients with retinal diseases, the introduction of biosimilars may become part of the evolving discussions of step therapy.
 
I think a retina specialist’s greatest concern is safety. We can see success with biosimilars in the other disciplines I mentioned, but in those settings clinicians are not administering medications directly into the eye. With biologics, the purification process is very important in manufacturing a safe product. That process is proprietary and companies with biosimilars are essentially trying to reverse engineer the product while not being subject to the same stringent clinical trial criteria required for FDA approval of biologics.^4,5 Eye specialists have expressed serious concerns that insufficient numbers of patients were included in the clinical trials of biosimilars to truly determine intraocular safety and that we may not uncover true safety events until the post-approval period, when more patients become exposed to these drugs.

The rate of intraocular inflammation was higher in patients treated with brolucizumab compared with patients who received aflibercept.⁶ In the study, severe vision loss was associated with intraocular inflammation, particularly occlusive retinal vasculitis. What patient-specific characteristics or risk factors inform your treatment decisions regarding targeted therapy for patients with wet AMD?

When a new medication becomes available, 2 pools of patients could potentially be treated with that agent. The first group is treatment-naive individuals with new disease. The much larger pool of potential recipients is patients receiving chronic anti-VEGF injection therapy. Within that population, you are specifically looking at patients who have had a suboptimal response to treatment regardless of the agent used and patients with an adequate response who have a high injection burden because the treatment interval could not be extended to a degree satisfactory to the patient and/or clinician.
 
I tend to be a bit more conservative in my response to the approval of a new agent and brolucizumab is a prime example of why. In clinical trials of brolucizumab, some patients experienced significant loss of vision as a result of intraocular inflammation and in the most extreme cases, patients experienced retinal vasculitis and/or retinal vascular occlusion.^7-9 This severe vision loss was not uncovered until the early period following its approval by the FDA. To guide future treatment decisions, a retrospective analysis of reports from 10 ophthalmology group in the United States evaluated demographics and clinical and imaging information specific to patients with ocular complications following treatment with brolucizumab (all 12 patients were women and some had a history of systemic autoimmune disease.)¹⁰ Ultimately, however, it is difficult to predict which patients will have an inflammatory autoimmune response to therapy with brolucizumab. 
 
Because of these concerns, I tend to use brolucizumab very sparingly, especially since many acceptable alternatives are available. I do have a handful of patients for whom all other therapeutic options, including photodynamic therapy, have failed. Ultimately, patients such as these need to decide if they are willing to accept potential risks of brolucizumab therapy and undergo treatment. Thankfully, my patients are stable and still receiving therapy with brolucizumab, but it is considered a third- or fourth-line agent due to safety concerns.

Standard maintenance dosing intervals for ranibizumab, aflibercept, and brolucizumab are every 4 weeks, 8 weeks, and 12 weeks, respectively. To what extent does frequency of administration impact treatment choice? When and how do you use treat-and-extend dosing?

In the real world, the treatment interval used in the pivotal trials and ultimately listed on the package insert does not have an impact on provider choice, because the majority of retina specialists follow a treat-and-extend protocol. With the treat-and-extend protocol, we administer injections monthly until a patient’s disease process is stable based on OCT, visual acuity, and the patient’s subjective response. Once that plateau is reached, we try to stretch out the treatment interval regardless of what agent the patient is receiving.^11-14 I extend therapy in 2-week intervals, so if a patient reaches that point of stability at 4 weeks, then we will try a 6-week interval and reassess the situation in hopes of extending to an 8-week treatment interval. My goal is usually 12-week intervals if the patient can tolerate it, but there is a lot of variability in terms of individual retina specialists’ treatment paradigms, when they decide to start extension, whether they extend by 1-week or 2-week intervals, and if they cap intervals at 8 weeks, 12 weeks, or even longer. Treatment is tailored to each patient based on response to treatment and personal preference. At the end of the day, there was an attempt through clinical trials and evaluation of drug intervals to homogenize the management approach to a very heterogeneous disease process. However, the key to disease management is to tailor the treatment regimen to a particular patient.

Even during the maintenance phase of treatment, patients may experience a recurrent retinal hemorrhage or develop new intraretinal or subretinal fluid between treatments. These adverse events would prompt a shortening of the treatment interval, even for patients who were previously stable. There is a bit more urgency to treating hemorrhage than serous fluid buildup; blood is more toxic to the photoreceptors and can have serious consequences such as permanent vision loss. When a hemorrhage occurs, the treatment interval may be cut in half or automatically scaled back to monthly injections, whereas when recurrent fluid changes are observed, we might only shorten the treatment interval by 1 or 2 weeks. Regardless of the issue, once the patient is stable, we will try to re-extend the treatment interval again. With the treat-and-extend approach, there is no definitive algorithm to follow so there may be high variability in how it is handled.

This Q&A was edited for clarity and length.

Disclosure

Ehsan Rahimy, MD, reported affiliations with Regeneron Pharmaceuticals, Inc., Genentech, Inc., and AbbVie, Inc.

References

1. Varadaraj V, Lesche S, Ramulu PY, Swenor BK. Reading speed and reading comprehension in age-related macular degeneration. Am J Ophthalmol. 2018;186:P138-P143. doi:10.1016/j.ajo.2017.11.026

2. Kleiner RC, Enger C, Alexander MF, Fine SL. Contrast sensitivity in age-related macular degeneration. Arch Ophthalmol. 1988;106(1):55-57. doi:10.1001/archopht.1988.01060130061028

3. Vemala R, Sivaprasad S, Barbur JL. Detection of early loss of color vision in age-related macular degeneration – with emphasis on drusen and reticular pseudodrusen. Invest Ophthalmol Vis Sci. 2017;58(6):247-254. doi:10.1167/iovs.17-21771

4. Kvien TK, Patel K, Strand V. The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems. Semin Arthritis Rheum. 2022;52:151939. doi:10.1016/j.semarthrit.2021.11.009

5. Kapur M, Nirula S, Naik MP. Future of anti-VEGF: biosimilars and biobetters. Int J Retin Vitr. 2022;8:2-8. doi:10.1186/s40942-021-00343-3

6. Frank H, Tomohiro I, Maruko I, SriniVas S. A consensus on risk mitigation for brolucizumab in neovascular age-related macular degeneration: patient selection, evaluation, and treatment. Retina. 2022;42(9):1629-1637. doi:10.1097/IAE.0000000000003556

7. American Society of Retina Specialists. Member update: Novartis-appointed safety review committee reports initial brolucizumab findings. June 4, 2020. Accessed August 8, 2022. https://www.brolucizumab.info/sites/brolucizumab_info/files/2020-07/ASRS_SRC_report.pdf 

8. Jain A, Chea S, Matsumiya W, et al. Severe vision loss secondary to retinal arteriolar occlusions after multiple intravitreal brolucizumab administrations. Am J Ophthalmol Case Rep. 2020;18:100687. doi:10.1016/j.ajoc.2020.100687

9. Monés J, Srivastava SK, Jaffe GJ, et al. Risk of inflammation, retinal vasculitis, and retinal occlusion-related events with brolucizumab: post hoc review of HAWK and HARRIER. Ophthalmology. 2021;128(7):P1050-P1059. doi:10.1016/j.ophtha.2020.11.011

10. Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127(10):P1345-P1359. doi:10.1016/j.ophtha.2020.04.017

11. Kertes PJ, Galic IJ, Greve M, et al. Efficacy of a treat-and-extend regimen with ranibizumab in patients with neovascular age-related macular disease: a randomized clinical trial. JAMA Ophthalmol. 2020;138(3):244-250. doi:10.1001/jamaophthalmol.2019.5540

12. Matsumoto H, Morimoto M, Mimura K, Ito A, Akiyama H. Treat-and-extend regimen with aflibercept for neovascular age-related macular degeneration: efficacy and macular atrophy development. Ophthalmol Retina. 2018;2(5):462-468. doi:10.1016/j.oret.2017.09.002

13. Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y; on behalf of the ALTAIR Investigators. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: a randomized controlled trial. Adv Ther. 2020;37(3):1173-1187. doi:10.1007/s12325-020-01236-x

14. Matsumoto H, Hoshino J, Mukai R, Nakamura K, Akiyama H; on behalf of the ALTAIR Investigators. One-year results of treat-and-extend regimen with intravitreal brolucizumab for treatment-naïve neovascular age-related macular degeneration with type 1 macular neovascularization. Sci Rep. 2022;12:8195. doi:10.1038/s41598-022-10578-1

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