Dosing Variability Risk Could Be High With Aflibercept PFS

Roger A. Goldberg, MD, MBA

A marketed syringe of the most popular anti-VEGF therapy in the US could be inconsistently dosed on the basis of its industrial design, according to a study.

Roger A. Goldberg, MD, MBA, Vitreoretinal Specialist with Bay Area Retina Associates, presented evidence showing a high risk of overdosing an aflibercept pre-filled syringe (PFS) based on its design in a session at the American Academy of Ophthalmology (AAO) 2021 Meeting in New Orleans this week.

Intravitreal anti-VEGF injection use has grown “dramatically” in recent years, Goldberg noted—more than doubling in use in the US annually from 2012 to 2018, as the highly efficacious drug class has received expanded indications from the Food and Drug Administration (FDA) and is thus more available to an increasing patient population.

“And aflibercept is the current market leader,” Goldberg said. “It accounts for nearly $3 billion of Medicare Part B spending—it is the number 1 drug by Part B spend—which if you back-calculate from the average sales price is about 1.5 million injections per year in the Medicare Fee For Service population.”

Added with other federally-funded programs and commercial-based prescriptions, there is approximately 2.5 million aflibercept injections in the US annually.

The perspective of preparing a syringe of the formulation therapy, Goldberg explained, an approximate minute spent filling a vial equates to about 2.5 million minutes, or almost 5 years, spent annually preparing the product for injection. Thus, the FDA approval of aflibercept PFS in August 2019 was expected to provide a more efficient mean of treatment storage and delivery.

Part of the FDA approval process for aflibercept PFS required a usability study observing a single injection in ≥30 patients. “Regeneron completed that study, leading to approval,” Goldberg said. “But was it efficient?”

Goldberg cited post-trial patient feedback in a case series showing reports of transient central retinal artery occlusions and an inability to see among patients who self-administered aflibercept PFS. He also noted FDA Adverse Event Reporting System (FAERS) data shows approximately 1100 relevant adverse event reports associated with aflibercept, as well as another 160 “device use issue” reports associated with the drug on FAERS since late 2020.

In March 2021, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee shared a communication noting a 7-fold increase in intraocular pressure (IOP) elevation in patients administering aflibercept PFS vs luer-lock syringe. The committee cited an “incorrect handling and preparation of the syringe.”

Among the reasons for such outcome variability between the standard syringe and PFS is the difference in proportions. Aflibercept PFS syringes feature an internal diameter 1.7 mm wider than even ranibizumab PFS syringes. What’s more, the former has a dose mark line that is 0.75 mm—a size 3 times greater than the ranibizumab PFS syringe.

“That alone can account for a 24 mcL difference, just in the thickness of the dose mark,” Goldberg said.

Goldberg and colleagues sought to observe the accuracy of PFS syringe delivery volumes. They took 15 empty syringes of both ranibizumab and aflibercept PFS—with multiple lot numbers—and filled each with 200 mcL purified water. Then, they measured volume by mass dispensed into a weighing cup.

They conducted multiple dose-setting scenarios—first being compliant with instructed filling for each syringe, then filling the syringes based on cone tip location at each of PFS syringe’s dose marks. Each of the 5 scenarios selected were tested 3 times.

Their study showed compliance with instructed filling use provided a high degrees of accuracy across the aflibercept and ranibizumab PFS platforms. However, the dose mark thickness on the aflibercept PFS syringe could lead to a 50% overdose versus the intended 50 mcL volume. Aligning doses based on the syringe’s cone tip, investigators added, could lead to a 120% increase from the intended volume.

Goldberg concluded that clinicians should adhere to instructed filling use to minimize the high risk of dose volume errors associated with aflibercept PFS. “And industrial design, even for something as simple as a syringe, actually matters,” he said.

Among Goldberg’s disclosures were research grants with Aerie, Allergan, Apellis, Genentech, Grayburg, Neurotech, Ribomics, Santan, Unity Biotechnology, and Zeiss Meditec. He additionally received consulting fees from Allergan, Apellis, Genentech, Regeneron, Unity, and Zeiss.

The study, “Dosing Errors with Aflibercept Pre-filled Syringe (PFS),” was presented at AAO 2021.