Regulatory Decision Summary for Eylea

The original Supplement to a New Drug Submission (SNDS) (Control #278211) was filed to obtain market authorization for a new indication for Eylea in preterm infants for the treatment of retinopathy of prematurity (ROP).

Based on the review of the data in this SNDS, Health Canada issued a Notice of Compliance with Conditions -Qualifying Notice (NOCc-QN) on March 13, 2025. In their response to the NOCc-QN dated March 13, 2025 and to a clarification request dated April 29, 2025, the sponsor provided a “Letter of Undertaking” and “Letter of NOCc Policy-Sponsor Consent” on April 30, 2025.

The retinopathy of prematurity (ROP) is a proliferative disorder characterized by incomplete vascularization and pathological neovascularization in preterm infants. It is a leading cause of blindness/severe visual impairment in childhood worldwide. Current standard of care, laser treatment, causes permanent loss of peripheral visual field and is associated with high myopia. It requires general anesthesia and adequate visualization of the retina, which may be problematic and not possible in some preterm infants with associated comorbidities.

Benefit

An open-label, multicenter, randomized, non-inferiority study (n = 75 in the aflibercept group; n = 38 in the laser group) showed that the response probability at Week 24 (primary endpoint, defined as the absence of active ROP and unfavorable structural outcomes in both eyes at Week 24) in the aflibercept group was numerically similar to the laser group. A supplementary analysis, which properly takes the limited sample size of laser group into account, showed the non-inferiority of aflibercept versus laser therapy. The absence of active ROP and structural abnormalities in both treatment arms were generally maintained through patients’ 2 years’ chronological age. 97% of subjects in both treatment arms showed their ability to fix and follow a 5 cm toy (an age-appropriate function outcome).

Compared to laser treatment, intravitreal (IVT) treatment of ROP is less invasive, more tissue and function-conserving, and may usually be administered under local anesthesia, which is considered an additional clinical benefit.

The sponsor’s initially proposed indication was considered too broad and included the ROP type that does not require treatment. The recommended indication has been restricted to reflect the study population included in the pivotal study and that requires treatment (i.e. type I ROP).

Risk

The proportion of subjects with any treatment-emergent adverse event (TEAE) was similar between aflibercept and laser treatments. Retinal hemorrhage, retinal detachment, conjunctival hemorrhage, injection site hemorrhage, intraocular pressure increased, eyelid edema, neurodevelopmental disorders were the most common adverse events reported in patients treated with IVT aflibercept. Recurrence of ROP is addressed by aflibercept re-treatment, close monitoring and will be further assessed through post-market pharmacovigilance activities. The risks associated with aflibercept treatment in patients with ROP have been captured properly in the Eylea Product Monograph.

Uncertainties

At this time, visual acuity (VA), the most important assessment to measure the integrity of the visual function and the most commonly used clinical measurement of visual function in the clinical trials, cannot be reliably measured at 2 years of age due to the level of general cognitive ability of subjects at this age. There is insufficient evidence to definitively exclude an association between aflibercept IVT use in preterm infants with ROP and neurodevelopmental impairment. Additionally, the long-term ocular safety profile of aflibercept in preterm infants with ROP remains to be characterized.

The Study 20275 is ongoing, and VA will be assessed at 5 years of age, a timepoint where VA as well as ocular and neurodevelopmental outcomes are more reliably assessable. The sponsor has committed to provide the final study report of study 20275 with the 5-year data as a confirmatory study to confirm treatment benefit and the safety profile of aflibercept used IVT in preterm infants for the treatment of ROP.

The sponsor’s response to NOC/c-QN/Letter of Undertaking is acceptable from a clinical perspective.

Risk Management Plan

The Core Risk Management Plan (RMP) v15.0 dated February 27, 2023 and the Canadian Addendum v8.0 dated August 9, 2023 for Eylea (aflibercept injection) was reviewed by the Marketed Health Products Directorate (MHPD) and was considered acceptable. The safety concerns associated with the use of aflibercept in preterm infants with ROP have been addressed in the Product Monograph and will continue to be monitored post-market as outlined in the RMP, with routine and additional pharmacovigilance activities through the ongoing long-term study 20275.

In the Letter of Undertaking, the sponsor agreed to include a safety review on events associated with ROP indication, including cases associated with potential neurodevelopment impairment for the next two annual summary safety reports, Periodic Benefit Risk Evaluation Report (PBRER) or Periodic Safety Update Report (PSUR) following the authorization of ROP indication in Canada.

Benefit/Risk

Considering the high risk of blindness for untreated ROP as well as totality of evidence provided in this submission, aflibercept have shown clinically promising evidence of efficacy in preterm infants for the treatment of ROP. The safety profile is generally acceptable and consistent with the known safety profile of this drug. The risks have properly been mitigated through wording included in the Product Monograph and pharmacovigilance activities. Residual uncertainties will be addressed through the 5-year efficacy and safety data from the ongoing extension study 20275 (confirmatory study).

Overall, the benefit-risk profile of Eylea (aflibercept injection) administered as a 0.4 mg IVT injection in preterm infants for the treatment of retinopathy of prematurity (ROP) with zone I (stage 1+, 2+, 3 or 3+), zone II (stage 2+ or 3+) or AP-ROP (aggressive posterior ROP) disease is considered favourable under the Notice of Compliance with conditions policy, when administered as per the conditions of use recommended in the approved Product Monograph.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

A Notice of Compliance with conditions (NOC/c) is recommended. For more information on the conditions issued, please refer to the Notice of Compliance with conditions (NOC/c) Website.

For further details about Eylea, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.