From August 2017 through February 2018, there was a relative increase in the number of reports of intraocular inflammation (IOI) following intravitreal aflibercept (Eylea; Regeneron) injection (2.0 to 8.3 reports per 10,000 vials distributed per month) compared to the 2014-2016 period (1-4 reports per 10,000 vials distributed per month) in the United States. No similar increase in reported cases was observed outside the United States. In response, Regeneron voluntarily conducted an extensive genealogical review of the manufacturing and distribution process for Eylea in the United States. No factors associated with the manufacturing of Eylea could be identified as related to the increased IOI reporting rate. However, this analysis identified that specific batches of syringes copackaged in certain lots of final Eylea kits distributed in the United States were associated with higher rates of IOI as compared to other syringe batches. These findings were communicated to the retinal physician community in February 2018, and distribution of the kits containing identified syringes was halted. As of April 2018, the overall rate of reported IOI returned to historical levels, and remained low through August 2018.

BACKGROUND AND PURPOSE

Intraocular inflammation is a recognized risk factor following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents, including Eylea injection. Consistent with the overall reported range for anti-VEGF agents,¹ the rate of IOI observed across Eylea pivotal phase 3 trials (neovascular age-related macular degeneration [AMD], diabetic macular edema [DME], retinal vein occlusion [RVO], and myopic choroidal neovascularization [CNV]) ranged from 0 to 30 per 10,000 injections (rate per 10,000 injections for duration of each study). Additionally, the incidences of IOI events were similar for every 4 week dosing of Eylea (28-30 per 10,000 injections) and ranibizumab (Lucentis; Genentech) injection (40 per 10,000 injections) for the treatment of patients with neovascular AMD from baseline through week 96 in the VIEW 1 and VIEW 2 studies.² This article describes the recent increase in reported rates of IOI associated with the commercial use of Eylea in the United States, the process used to analyze potential associated manufacturing and packaging factors, and the steps taken by Regneron related to these findings.

INCREASED RATE OF IOI IN THE UNITED STATES FOLLOWING EYLEA INJECTION: AUGUST 2017 – FEBRUARY 2018

Following the initial FDA approval of Eylea in November 2011 and subsequent approvals around the world, Regeneron Pharmaceuticals, Inc. and Bayer AG have assiduously monitored reports of adverse events, including IOI cases, following Eylea injections. In the United States, following the post-launch period, annualized rates of reported IOI have historically ranged from 1 to 4 per 10,000 vials distributed (Figure 1, top).

In August and September 2017, although still within the historical annualized range, there was an increase in the United States for reports of IOI following Eylea injections compared to 2015 and 2016 (Figure 1, top). This increased rate of IOI cases in the United States continued into February 2018, remaining within the historical range of reported rates of IOI (Figure 1, top panel). The initial and regular follow-up investigations did not reveal any issues with the manufacturing process. Nevertheless, Regeneron and Bayer increased the frequency of their joint review of the global safety information and broadened the investigation with specific focus on the course of IOI reporting rates for Eylea. From October 2017 through January 2018, the American Society of Retina Specialists (ASRS) issued communications to their membership about the increased reports of IOI following administration of Eylea including IOI reports as provided by Regeneron.

No similar increase in monthly cases was observed outside the United States (Figure 1, bottom). In Canada, reports of IOIs showed an increasing trend in early 2018, however there were no reported clusters of sterile endophthalmitis (defined as more than 5 IOI cases in 30 days per site).The increase in reports in early 2018 may have potentially been related to stimulated reporting based on heightened awareness of IOI reports, during which time a communication was released by the ASRS and the Canadian Retina Society. When reported IOI events were plotted by the injection date, the rates were in line with what has been reported historically in Canada.

PHARMACOVIGILANCE AND POSTMARKETING SURVEILLANCE

Regeneron and its codevelopment collaborator for Eylea, Bayer AG, continually collect and monitor adverse event reports, including reports of IOI, globally to assess for new safety signals of Eylea in an ongoing manner as part of routine postmarketing surveillance. Regeneron is required by law to follow all US Food and Drug Administration (FDA) regulations and guidance, and to comply with stringent FDA expectations relevant to any product complaint or adverse event reporting. The FDA has oversight of the Eylea manufacturing facilities and lines in support of distribution to US territories, and Regeneron must comply with their regulations and guidelines. All drug products undergo rigorous testing, including sterility and endotoxin level, to ensure they meet the quality and potency standards required by the FDA. All complaints received by Regeneron are evaluated, and Regeneron is obligated to show the FDA how product complaints have been addressed. Additionally, Regeneron is required to comply with Good Manufacturing Practice standards.

In ex-US territories outside the United States, Bayer supplies Eylea in more than 100 countries and is required by law to follow all local health authority regulations and guidance, including but not limited to the European Medicines Agency (EMA), the Japanese Pharmaceuticals and Medical Device Agency (PMDA), the Brazilian Health Regulatory Agency (ANVISA), the Australian Therapeutic Goods Administration (TGA), and HealthCanada. While multiple manufacturing facilities support the downstream filling and packaging for the Eylea program globally, only 1 manufacturing facility is jointly used by Regeneron and Bayer for bulk production and formulation of the active pharmaceutical ingredient and is therefore subject to inspections from the FDA as well as health authorities outside the United States. Bayer complies with stringent health authority inspections relevant to product complaints and adverse event reporting. All products undergo rigorous testing to ensure they meet the quality and potency standards required by the responsible health authorities. All complaints received by Bayer are evaluated, and regular information is provided to health authorities regarding how product complaints have been addressed.

OVERVIEW OF EYLEA MANUFACTURING PROCESS IN THE UNITED STATES

Figure 2 shows the sequence of Eylea manufacturing. A 10,000 L bioreactor produces one lot of Eylea drug substance (DS) sufficient to fill approximately 450,000 vials. This occurs in several steps. First, each lot of Eylea DS is split into approximately 5 equally sized batches, each of which is separately formulated with excipients to create a lot of Eylea formulated drug substance (FDS). Each lot of Eylea FDS produces either 3 lots each of approximately 30,000 Eylea drug product (DP) vials (filler 1) or one larger lot (approximately 90,000) of Eylea DP vials (filler 2). Filler 1 produces Eylea labeled drug product (LDP) vials for distribution both in the United States and outside the United States; filler 2 produces Eylea LDP vials for US distribution only. Each lot of Eylea LDP vials is then packaged by packagers 1 and 2 in the United States into a kit with additional components (syringe, injection needle, and filter needle). Each lot of packaged LDP kits is given a final lot number that is printed on the Eylea vial and on the carton. The syringe, injection needle, and filter needle each carry a separate lot number that is different from the Eylea vial and carton lot number.

GENEALOGICAL ANALYSIS

In response to the relative increase in reported IOI cases in the United States, Regeneron voluntarily conducted an extensive genealogical review of the manufacturing and distribution process for packaged LDP kits distributed for use in the United States.

Analysis of Factors Related to Eylea Manufacturing Process in the United States

All Eylea drug substance, regardless of where they are distributed, is made in the same facilities with the same equipment, bioreactors, purification columns, personnel, raw materials, procedures, release testing, and quality standards. Therefore, if the cases of IOI were associated with the bulk manufacturing process, it would be expected that an increased rate would have been observed across all lots distributed both in and out of the United States.

For factors specific to US drug supply, there was a systematic search for any common patterns. The scope of the investigation included the bioreactor itself, or the main DS, through the final distribution of packaged LDP kits for commercial sale and clinical use. Analysis of procedures, raw materials, filling sites, packaging and distribution sites, and quality standards was performed. The 6 packaged LDP kit lots with the highest rates of IOI in the United States came from 5 different DS bioreactors and 5 different FDS lots and had been filled by 2 fillers. Other packaged LDP kit lots with rates of IOI more typical of the 2015 and 2016 period were produced using the same equipment on the same filling lines and, in many cases, came from the same DS or FDS lots as these 6 final packaged LDP kit lots with the highest rates of IOI reports. This degree of variability indicated that there was not an association between the manufacturing of LDP vials and the reporting rates noted in this period.

Analysis of Factors Related to Eylea Kit Components in the United States

After producing LDP, Eylea vials are packaged into kits that contain external disposable components. In the United States, 3 disposable components (filter needle, injection syringe, and injection needle) are provided in the packaged LDP kit. The investigation identified an association of higher IOI rates with certain batches of syringes copackaged in specific lots of packaged LDP kits that were distributed in the United States. The identified syringes were distributed in a total of 8 Eylea final packaged lots, including the 6 with the highest reported IOI rates as well as lots ending in 104 and 105, which had not been distributed at the time of the initial investigation.

The syringe lot ending in 38 (packaged in kits with lot numbers ending in 76, 90, 92, 94, and 95) was associated with more than 7 reports of IOI per 10,000 vials distributed as of February 23, 2018 (the time of the investigation). The identified syringes were packaged in only 10% of the packaged LDP kits sold in the United States since January 2017, but they were associated with greater than 45% of the reported IOI cases in 2017 and 2018. Additionally, the syringe lot ending in 41 (packaged in kits with lot numbers ending in 93, 104, and 105) entered distribution more recently and, as of February 23, 2018, was already associated with an IOI reporting rate of more than 3.5 cases per 10,000 vials distributed. In contrast, other lots of syringes in distribution in 2017 were typically associated with IOI reporting rates of less than 2 cases per 10,000 vials distributed (Figure 3).

Outside of the United States, Eylea is marketed by Bayer in the form of LDP accompanied by a filter needle only. In accordance with its marketing authorizations (MA), syringes are not provided as part of the Eylea presentation. Apart from the MA in 12 selected countries (Finland, Bulgaria, Switzerland, Hungary, Portugal, Romania, Hong Kong, France, Italy, Czech Republic, Slovenia, and Slovakia), Bayer distributes a separate procedure pack that includes an injection needle and a syringe. The 2 identified syringe lots in the United States have never been supplied outside of the United States in these procedure packs.

COMMUNICATION WITH THE RETINAL PHYSICIAN COMMUNITY

On February 27, 2018, Regeneron communicated with the syringe manufacturer, Becton Dickinson, to initiate a collaborative effort to identify any potential causative factors related to the syringe. To date, no notable findings have been identified. On February 28, 2018, Regeneron sent a communication to the ASRS, FDA, and retina specialists recommending that practitioners not use the syringes from the identified lots and offering to exchange the Eylea kits containing these syringes.

From January 1, 2018 until February 28, 2018, the IOI reporting rate was 7.2 per 10,000 vials distributed. Within 1 month of this communication, more than 20,000 kits were returned, and the IOI reporting rate dropped significantly. The IOI monthly reporting rate per 10,000 vials distributed was 5.8 in March 2018, 2.6 in April 2018, and 1.2 in May 2018 and continued to decrease through August 2018 (Figure 4).

A follow-up communication was issued to retina specialists on May 1, 2018, informing them that as of April 2018, the IOI reporting rate had returned to historical levels of 1-4 reports per 10,000 vials distributed and remains within this range as of August 2018.

DISCUSSION

Based on the review of manufacturing and distribution data, no factors associated with the manufacturing of labeled drug product (LDP) could be identified as related to the increased IOI reporting rate. However, Regeneron’s analysis identified an association with specific batches of syringes copackaged in certain lots of final Eylea kits that were distributed in the United States. Historically, based on postmarketing surveillance, after the initial launch period, the annualized rate of reported IOIs has ranged from 1 to 4 cases per 10,000 vials. The rate of reported IOI among the Eylea kits copackaged with the identified syringes was 8-12 reports per 10,000 vials, while the rates for the Eylea kits without the identified syringes that were distributed at the same time generally remained within the historical range. As of April 2018, the overall rate of reported IOI has returned to historical levels of 1-4 reports per 10,000 vials.

Regeneron continues to monitor IOI rates and continues the investigation in collaboration with the syringe manufacturer, Becton Dickinson, to identify any potential causative factors that affected the identified lots but not the other lots of syringes. To date, no notable findings have been identified.

Overall, no new safety concerns related to the Eylea drug product can be identified from this review and the benefit-risk balance of Eylea remains unchanged. Regeneron and Bayer are committed to ensuring the safety of patients using their product and follows established procedures for monitoring safety. To report an adverse event or product complaint about any Regeneron product, including Eylea, contact the Regeneron medical information department at (855) 734-3648. Practitioners are also encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch , or call (800) FDA-1088. Outside the United States, the following website can be used to report adverse events to Bayer: http://pharma.bayer.com/en/treatment-care/report-a-side-effect . Moving forward, close surveillance will continue and the retina community will be informed in a timely fashion of all information regarding this investigation.

REFERENCES

1. Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;(8):CD005139.
2. Data on file. Regeneron Pharmaceuticals, Inc., Tarrytown, New York.