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Retinal Physician

Article

Managing Treatment Resistance in Neovascular Age-related Macular Degeneration

Novel therapies are on the horizon.

By: Asad F. Durrani, MD, Yoshihiro Yonekawa, MD
Retinal Physician September 1, 2023 Vol 20, Issue September 2023 Page(s): 18-21

From the Archives

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness for Americans aged 65 years and older according to the Centers for Disease Control and Prevention. Although neovascular AMD (nAMD) accounts for only 10% of AMD patients, the majority of severe vision loss associated with AMD is due to nAMD.1 Anti–vascular endothelial growth factor (anti-VEGF) therapy has remained the standard of care for nAMD since 2004 with the FDA’s approval of pegaptanib sodium (Macugen; Bausch + Lomb), and more so with the 2007 approval of ranibizumab (Lucentis; Genentech). Since that time, numerous anti-VEGF agents have been developed and used for the treatment of nAMD, including bevacizumab (off label, Avastin; Genentech), aflibercept (Eylea; Regeneron), brolucizumab (Beovu; Novartis), faricimab (Vabysmo; Genentech), ranibizumab-nuna (Byooviz; Biogen), and ranibizumab-eqrn (Cimerli; Coherus).

Despite the efficacy of anti-VEGF agents in many patients, a subset of patients experiences incomplete treatment response, with persistent intraretinal or subretinal fluid (SRF) and associated vision loss. The 2-year results from the Comparison of Age-related Macular Degeneration Treatment Trials demonstrated that 51.5% of eyes receiving monthly ranibizumab and 67.4% of eyes receiving monthly bevacizumab had persistent fluid on optical coherence tomography (OCT).2 Although the proportion of eyes with persistent fluid receiving monthly aflibercept was lower, VIEW-2 demonstrated that 19.7% of these eyes still had fluid on OCT at 1 year.3 This represents a significant number of patients with inadequate response to our most commonly used treatments.

MECHANISM

The mechanism of treatment resistance in nAMD is not fully understood and is thought to be multifactorial. Inaccurate diagnosis may play a role, because some patients diagnosed with nAMD have polypoidal choroidal vasculopathy (PCV), which is a variant of nAMD that tends to require photodynamic therapy (PDT) for optimal response in a subset of patients.4,5 Patients with central serous retinopathy without choroidal neovascularization may also be misdiagnosed with treatment-resistant nAMD. Although genetic testing is not currently used as a part of treatment for nAMD, variants have been described in the literature with decreased responsiveness to anti-VEGF therapy.6 Tolerance and tachyphylaxis also play a role in treatment resistance. Tolerance occurs due to increased expression of VEGF and its receptors or due to the development of neutralizing antibodies to anti-VEGF therapy.7 Finally, compensatory angiogenic or inflammatory pathways likely play a key role in the pathogenesis of treatment resistance. Understanding these potential causes of treatment resistance is critical to developing strategies to effectively manage these patients.

SWITCHING AGENTS

The most common strategy used by retina specialists to counter treatment resistance is to switch anti-VEGF agents. This strategy directly addresses the issue of tachyphylaxis, which has been shown to occur with anti-VEGF agents,8-10 where a decrease in response to a drug occurs following its successive administration. Incomplete response with initial treatment is also managed with switching anti-VEGF agents. This is especially true for bevacizumab, which is generally the least efficacious of the currently used anti-VEGF agents, but the initial drug used in many patients due to fail-first therapy mandated by commercial payors. Evidence is mixed for switching from bevacizumab to ranibizumab. Kent et al11 showed a significant improvement in visual acuity and anatomic outcomes in 87 eyes, whereas Stepien et al12 showed no difference in visual acuity or injection burden in 84 eyes. The evidence for switching from bevacizumab to aflibercept is more clear, with a prospective clinical trial and multiple retrospective studies demonstrating improvement in BCVA and anatomic outcomes.13-15 Although the switch from bevacizumab to aflibercept shows clear benefits, Chakravarthy et al demonstrated in their study of 454 switchers and 750 matched nonswitchers that no change in visual acuity was observed in eyes switched from ranibizumab to aflibercept compared to those continued on ranibizumab.16 Despite no improvement in visual acuity, Granstam et al demonstrated an improvement in anatomic outcomes in those switched from ranibizumab to aflibercept, suggesting there may be some benefit to this strategy.17 Finally, in patients experiencing treatment resistance to aflibercept, switching to ranibizumab has been shown to cause modest improvements in visual acuity and anatomic outcomes.18 Anecdotally, the authors have also utilized a strategy of cycling injections with ranibizumab and aflibercept with some benefit in treatment-resistant patients. Although visual improvement may be limited in the aforementioned “switch” studies, since these are eyes with chronic intraretinal and/or SRF, there is often an anatomic benefit, which allows retina specialists to extend intervals and decrease injection burden for these patients.

Figure 1. A patient with neovascular age-related macular degeneration (nAMD) treated with aflibercept every 4 to 6 weeks for their last 44 injections with persistent subretinal fluid (A). The same patient following 3 faricimab injections 6 weeks apart with complete resolution of subretinal fluid (B). Vision remained stable.
Figure 1. A patient with neovascular age-related macular degeneration (nAMD) treated with aflibercept every 4 to 6 weeks for their last 44 injections with persistent subretinal fluid (A). The same patient following 3 faricimab injections 6 weeks apart with complete resolution of subretinal fluid (B). Vision remained stable.

In the last few years, novel anti-VEGF agents have come to market that offer new options for treatment-resistant patients. In 2019, the FDA approved brolucizumab for the treatment of nAMD after the HAWK and HARRIER trials demonstrated noninferiority to aflibercept. Real-world data suggest positive visual acuity and anatomic results with decreased treatment burden in eyes resistant to aflibercept switched to brolucizumab.19-21 Brolucizumab, however, has fallen out of favor with most retina specialists given its unacceptable rate of intraocular inflammation, including vision-threatening retinal vasculitis.22,23 In 2022, the FDA approved faricimab, the first bispecific antibody, for the treatment of nAMD. Faricimab has the benefit of inhibiting VEGF as well as angiopoietin-2 (Ang2), which may prove useful in treatment resistant eyes. The 6-month results from the TRUCKEE study are encouraging as they suggest improvement in visual acuity and anatomic parameters with the potential to further extend treatment resistant patients.24

INCREASING DOSE OR FREQUENCY

Tolerance to specific anti-VEGF agents can also be addressed in 2 different ways: decreasing the interval of administration or increasing its dosage. Given the efficacy of aflibercept with every-4-week dosing, more frequent dosing is a potential option for patients with treatment-resistant nAMD. Schneider et al demonstrated in their single-arm prospective study of 22 eyes that every-other-week aflibercept resulted in modest improvements in visual acuity and anatomic outcomes at 14 weeks in eyes with persistent SRF.25 Although these results are promising, reimbursement remains a challenge, with most carriers only covering injections given 28 days apart.26 In terms of increased dosing of anti-VEGF agents, Regeneron presented data in 2023 from the PULSAR study on high-dose (8 mg) aflibercept for the treatment of nAMD. These results demonstrated that longer dosing intervals at 12 weeks and 16 weeks were comparable to standard dose aflibercept at 8-week intervals.27 Although data are not yet available on outcomes in treatment-resistant patients, a higher dose aflibercept may have a greater drying effect compared to standard dose aflibercept, giving retina specialists another weapon to battle treatment resistance.

ADJUVANT STEROID THERAPY

Choroidal neovascularization is thought to have an inflammatory component in addition to its angiogenic component. Therefore, retina specialists can consider supplementing anti-VEGF therapy with intravitreal corticosteroids.26 Todorich et al demonstrated in their study of 18 patients with treatment-resistant nAMD that dual therapy of an anti-VEGF agent with a dexamethasone intravitreal implant results in a decrease in central foveal thickness, with 33% of patients gaining 1 or more lines of vision.28

PHOTODYNAMIC THERAPY

Prior to the development of anti-VEGF therapy, PDT was first-line treatment for nAMD after the TAP study demonstrated that a higher percentage of eyes maintained vision with PDT compared to placebo. The ANCHOR study in 2009 showed that anti-VEGF was more efficacious than PDT; however, combination anti-VEGF and PDT therapy remains an excellent option for eyes with treatment-resistant nAMD. This combined strategy may be most effective in patients with “treatment-resistant AMD” who actually have PCV, which may represent up to 25% of all patients with nAMD.4 However, the HARBOR study a decade ago showed that high-dose ranibizumab (0.5 mg vs 2 mg) did not result in superior outcomes.29

AQUEOUS SUPPRESSION

Topical dorzolamide-timolol may be a useful adjuvant in treatment-resistant eyes, because both medications decrease aqueous production and therefore decrease the outflow of anti-VEGF therapy through the trabecular meshwork. Dorzolamide may also improve exudation by its effect on retinal pigment epithelial pump function, leading to fluid egress from the retina into the choroid. Hsu et al demonstrated in their randomized placebo-controlled clinical trial that there was a significant improvement in central subfield thickness in eyes treated with dorzolamide-timolol while receiving anti-VEGF injections.30 However, there was no improvement in visual acuity in this trial. Given its relatively low-risk safety profile, topical therapy with dorzolamide-timolol may be beneficial in patients with treatment-resistant nAMD undergoing anti-VEGF therapy.

FUTURE DIRECTIONS

Anti-VEGF-A therapy has been the mainstay of treatment for nAMD for the last 2 decades, and an important potential long-term delivery of anti-VEGF therapy is gene therapy, which is being developed through multiple potential routes of administration, including intravitreal, subretinal, and suprachoroidal. Many novel therapies targeting other pathways are also on the horizon. A phase 2 clinical trial testing blockade of VEGFs C and D with the novel drug OPT-302 (Opthea) in combination with ranibizumab was recently completed and demonstrated improvements in visual acuity compared to ranibizumab alone.31 Tyrosine kinase inhibition is another potential therapeutic target, because the VEGF receptor is a tyrosine kinase that initiates an intracellular signaling cascade once activated.32 Multiple tyrosine kinase inhibitors, including intravitreal, suprachoroidal, and even topical therapies, are in phase 1 and 2 clinical trials and represent a promising new treatment option for treatment-resistant disease. Senolytic therapy with UBX1325 (Unity Biotechnology), a novel Bcl-xL inhibitor that disrupts apoptosis, is also under investigation for treatment-resistant nAMD with the theory that nAMD is an age-related process driven by senescence. Finally, genetic testing is not typically obtained when treating patients with nAMD, however, given the association of specific genetic variants with treatment resistance and decreasing costs of genetic testing, retina specialists may one day obtain genetic testing to personalize the choice of agent for patients with treatment-resistant nAMD. RP

Asad F. Durrani, MD, is a vitreoretinal surgery fellow, and Yoshihiro Yonekawa, MD, is an adult and pediatric vitreoretinal surgeon, at the Wills Eye Hospital, Mid Atlantic Retina, and Thomas Jefferson University in Philadelphia, Pennsylvania. Dr. Durrani reports consultancy to Regenxbio. Dr. Yonekawa reports consultancy to Alcon, Bausch Health, EyePoint Pharmaceuticals, Regeneron, and Versant Health, as well as being a principal investigator for Genentech, Janssen, Kodiak Sciences, and Regeneron. Reach Dr. Durrani at adurrani@midatlanticretina.com. Editor’s note: Hear discussion of this article on the Retina Podcast at retinapodcast.com .

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