In August, Regeneron released early results of the 106-subject phase 2 CANDELA proof-of-concept trial of intravitreal aflibercept (Eylea) 8 mg in treatment-naïve neovascular AMD (nAMD). Patients were randomized to receive reformulated 8-mg aflibercept vs control 2-mg aflibercept. Although the results are preliminary and incomplete, early findings demonstrate some anatomic benefit. After 3 monthly intravitreal injections, a higher proportion of patients in the aflibercept 8 mg group had no retinal fluid (43.4%, n=23/53) compared to patients treated with aflibercept 2 mg (26.4%, n=14/53; P=.067) (week 16 preliminary endpoint). There were no significant visual acuity differences, however, between the 2 groups, but this study will continue to treat and follow anatomic and vision outcomes for a longer duration. At 16 weeks, 8-mg aflibercept was found to be safe with comparable adverse and serious ocular adverse event rates to aflibercept 2 mg. In particular, there were no adverse events of intraocular inflammation (IOI) or occlusive vasculitis during this short window of follow-up. It’s notable, however, that the total number of patients is not likely adequately powered to assess accurate IOI rates.

We asked 2 experts in the field of clinical research, Dr. Dilsher Dhoot and Dr. David Eichenbaum, to comment on the preliminary data. What excites them about the data? What are they concerned about? What are their predictions for the phase 3 trial and how does this potentially fit unmet needs in the treatment of exudative AMD?

Given the early results of this study without a formal presentation to date, Regeneron respectfully opted to decline a formal interview until further data were available. However, in their statement below, Regeneron sheds some light on why this trial was initiated.

Dilsher S. Dhoot, MD

California Retina Consultants, Santa Barbara, California

A larger population and a greater follow-up period would be helpful in evaluating the true benefit of this higher dosage of aflibercept as well as evaluating for safety and tolerability of the higher dose. The phase 3 trials will help expand on these results.

The advantage to a higher dosage of aflibercept in my opinion would center around 2 desirable unmet needs, durability and efficacy for patients with nAMD. The greater dosage may result in a longer duration within the eye, allowing patients to be extended for a greater amount of time. The greater concentration of aflibercept may also allow for greater drying ability, as suggested by the higher proportion of fluid-free patients at 16 weeks in this trial.

The HARBOR trial of high-dose ranibizumab (Lucentis; Genentech) did not demonstrate significant benefit, and hence we don’t use 2-mg Lucentis. In HARBOR, however, patients were treatment-naive, and within this population there was no difference with the higher-dose ranibizumab. Other studies have suggested higher-dose ranibizumab is beneficial, such as SAVE and LAST; however, these trials were done in recalcitrant nAMD populations. Aflibercept has a higher binding affinity and also binds to placental growth factor. These factors may contribute to the positive anatomic results in this trial.

I anticipate favorable results in phase 3 with respect to anatomic outcomes and durability. I’m less optimistic that we will see superiority when it comes to vision, but certainly we will see noninferiority. Furthermore, I do not expect greater adverse events. Aflibercept has a safety profile in line with other anti-VEGF agents, and I predict similar safety outcomes in the phase 3 trial.

I’m most interested in seeing the anatomic data in the patients dosed every 16 weeks. Reducing patient burden and maintaining anatomic outcomes at 16 weeks with aflibercept 8 mg compared to on-label dosing with aflibercept 2 mg would be a meaningful outcome for patients and providers.

This is a very exciting time to be practicing retina. There is a robust development pipeline in retina and we look forward to greater treatment options for our patients that improve on the amazing drugs we already have in our toolkit. The unmet needs in wet AMD therapy center on efficacy and durability. The lower hanging fruit for efficacy seems to be anatomic outcomes, with vision being a more challenging bar to raise. Newer medications with greater durability are emerging and it is very likely aflibercept 8 mg will be among this pack.

David Eichenbaum, MD

Retina Vitreous Associates of Florida, Tampa, Florida

The CANDELA study has very short follow-up with very few doses for a long-term disease and a small number of subjects. Increased molar concentration of anti-VEGF potentially treats exudation more completely and perhaps controls exudation with more durability. Brolucizumab (Beovu; Novartis), which has a higher molar concentration of anti-VEGF monotherapy activity than aflibercept 2 mg, showed superiority in retinal drying in nAMD in the dose-matched component of the HAWK/HARRIER series. There were also design and molecular weight differences between the aflibercept trap glycoprotein and smaller brolucizumab single-chain antibody fragment, but some of the anatomic superiority of the brolucizumab in HAWK/HARRIER matched-phase may be attributable to the greater molar concentration of anti-VEGF in the brolucizumab group.

If the proof-of-concept signal of superiority seen in this phase 2 aflibercept study is replicated in the fully enrolled, ongoing, larger phase 3 programs, it is plausible that the high-dose aflibercept molecule may have achieved a “critical mass” of anti-VEGF molar concentration to yield superiority at a concentrated dose. It is possible that Lucentis 2 mg as studied in HARBOR did not achieve that critical mass. It is also possible that the molecular design and affinity differences between aflibercept and the ranibizumab monoclonal antibody fragment may confer greater potency to aflibercept, which could be meaningfully amplified at a higher concentration.¹

I am not sure that the phase 3 results will replicate the phase 2 results. There have been positive data for high-dose aflibercept for recalcitrant nAMD disease presented in some retrospective series,^2,3 but no data support superiority of high-dose aflibercept in either nAMD or DME. Regardless, the retrospective published data and these new phase 2 data are encouraging, and I look forward to the phase 3 results.

I would continue to be vigilant about reported Antiplatelet Trialists’ Collaboration (APTC) and IOI data in the phase 3 data set, although there is no signal of an increase in these adverse events in the phase 2 data. The RISE/RIDE series reported a nonstatistically significant trend toward increasing systemic APTC adverse events in diabetics with ranibizumab 0.5 mg vs Lucentis 0.3 mg,⁴ and it will be important that high-dose aflibercept group mirrors the excellent aflibercept 2 mg and ranibizumab 0.3 mg systemic safety profile in vasculopathic diabetic patients. Brolucizumab was associated with greater IOI incidence in both the HAWK/HARRIER trial⁵ as well as in real-world series.⁶ Although the etiology of this adverse event is unclear, one theory is that it has to do with a higher molar concentration of drug. In the phase 3 study, I am interested to see a clear signal of anatomic superiority with high-dose aflibercept with preservation of the benign local and systemic safety profiles we know and love in our commercial anti-VEGF experience.

These valuable studies will write the second chapter on whether “more is better” in anti-VEGF monotherapy. They are meaningful trials to close out the 20-year chapter on anti-VEGF large-molecule treatment administered in aqueous solution. They will help fill in one of the few remaining gaps we have in our understanding of monotherapy, which is whether we have reached a safe and maximally efficacious dosage ceiling. Our retina pipeline will continue to depend on anti-VEGF treatment, but we are looking at late-phase polymeric delivery, combination with additional mechanisms of action, implants to deliver anti-VEGF, and gene therapy that converts the eye to an anti-VEGF biofactory. It is likely that one or more of these approaches will open the next chapter of antiangiogenic therapy in nAMD and diabetic macular edema.

REGENERON STATEMENT

The development of a higher concentration aflibercept formulation was initiated to provide an option for a higher molar dose. The concentration and formulation for high-dose intravitreal aflibercept injection was selected utilizing several factors, including in vitro data and preclinical studies including toxicology. Half-life analysis of free aflibercept showed a dose response in the vitreous, supporting the pharmacologic use of higher doses of intravitreal aflibercept injection.⁷ After an 8-mg dose, modeling studies suggested that a substantially higher proportion of patients may maintain a minimally effective vitreous concentration at 12 weeks compared to a 2 mg dose. RP

REFERENCES

1. Stewart MW. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br J Ophthalmol. 2012;96(9):1157-1158. doi:10.1136/bjophthalmol-2011-300654
2. Smith SD, Kapoor K, Wagner A. High-dose, High-frequency intravitreal aflibercept for wet AMD. Invest Ophthalmol Vis Sci. 2020;61(7):4234.
3. You QS, Gaber R, Meshi A, et al. High-dose high-frequency aflibercept for recalcitrant neovascular age-related macular degeneration. Retina. 2018;38(6):1156-1165. doi:10.1097/IAE.0000000000001726
4. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013-2022. doi:10.1016/j.ophtha.2013.02.034
5. Dugel PU, Singh RP, Koh A, et al. HAWK and HARRIER: ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2021;128(1):89-99. doi:10.1016/j.ophtha.2020.06.028
6. Enríquez AB, Baumal CR, Crane AM, et al. Early Experience With Brolucizumab Treatment of Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2021;139(4):441-448. doi:10.1001/jamaophthalmol.2020.7085
7. Do DV, Rhoades W, Nguyen QD. Pharmacokinetic study of intravitreal aflibercept in humans with neovascular age-related macular degeneration. Retina. 2020;40(4):643-647. doi:10.1097/IAE.0000000000002566