Intraocular inflammation as a major adverse event of anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration: from clinical trials to real-world practice

KEYWORDS:

• Age-related macular degeneration
• anti-vascular endothelial growth factor
• safety
• intraocular inflammation

1. Introduction

Neovascular age-related macular degeneration (AMD) is a vision-threatening condition requiring long-term treatment. Therefore, both the efficacy and safety of the treatment modalities are critically important. Anti-vascular endothelial growth factor (VEGF) therapy is a highly effective first-line treatment for neovascular AMD. Although anti-VEGF therapy has a good safety profile, it is not entirely devoid of safety concerns.

Clinical trials are essential for introducing new treatment agents and enabling substantial evaluation of their efficacy and safety. However, clinical trials have strict eligibility criteria [1–3], and patients who do not meet these criteria are excluded from the study, which limits the evaluation of safety in patients who fall outside the eligibility criteria. In a previous study, 44.7% of real-world patients did not meet the eligibility criteria of VIEW studies [4]. Another limitation of clinical trials is their limited patient inclusion, which can lead to underpowered safety issue detection. Therefore, in certain instances, additional safety considerations could have been identified through more detailed analyses that were not reported as key findings in clinical trials [5,6] or through studies based on real-world data [7].

In this editorial, I discuss the intraocular inflammation (IOI) issue associated with anti-VEGF therapy for neovascular AMD.

2. Intraocular inflammation

IOI is a well-known adverse event related to the intravitreal injection of anti-VEGF [8,9]. If IOI occurs at a high frequency during clinical trials for new drug development, it can pose a significant obstacle to obtaining approval for the medication. In phase 3 clinical trials of abicipar pegol, IOI occurred in approximately 15% of the study participants [10]. As biologics are synthesized through the cellular metabolic processes, host-derived impurities may get incorporated into the final product [11]. These host-derived impurities have been suspected as a major cause of IOI after abicipar pegol therapy [12]. Although the manufacturing process was modified to reduce host-derived impurities and the inflammation incidence [12], the drug still lacks Food and Drug Administration approval.

Although ocular safety issues were raised upon the introduction of ranibizumab and aflibercept, these were quickly disproven. However, the advent of brolucizumab has brought IOI, a complication of anti-VEGF therapy, to the forefront of ocular safety concerns [13]. In the HAWK and HARRIER studies, which were conducted for the introduction of brolucizumab, the frequency of IOI and retinal artery occlusion observed in patients treated with brolucizumab was slightly higher than in those treated with aflibercept [2]. However, the difference was not statistically significant, and consequently, brolucizumab has become available in real-world practice.

In real-world settings, the occurrence of IOI has garnered great attention [13] as many patients undergo treatment, prompting efforts to analyze risk factors and establish safe methods for drug administration [7]. One notable observation is that patients with a history of IOI and/or retinal vascular occlusion within 12 months prior to brolucizumab initiation exhibit an increased risk of these complications following brolucizumab treatment [7]. In the HAWK and HARRIER studies, patients with a recent history of steroid use for ocular inflammation or other retinal diseases that could limit the potential to gain visual acuity, such as retinal vascular occlusion, were excluded. Consequently, it was not possible to accurately evaluate the safety of brolucizumab in these patients.

The exact cause of drug-related IOI in anti-VEGF therapy has not been fully elucidated. Anderson et al. suggested the patient’s susceptibility, anti-VEGF medication or its associated suspension, silicone oil, and protein aggregation as potential etiologies of acute-onset sterile inflammation [9]. Two causes of IOI following brolucizumab injection have been proposed: delayed hypersensitivity resulting from local antibody reactions and factors such as prior anti-VEGF treatment, previous IOI events, human leukocyte antigens, and comorbidities [14]. Brolucizumab may change the behavior of retinal endothelial cells, subsequently leading to IOI [15]. Recent research suggests that brolucizumab anti-drug antibodies (ADAs) are significantly prevalent in a typical ophthalmic patient population [16]. However, clinical trials have not considered evaluating these ADAs as a key outcome.

In the HAWK and HARRIER studies, injections at intervals of less than 8 weeks were not permitted after the loading injection [2]. In clinical practice, more frequent injections may be necessary for patients who show a limited response. In the recently conducted MERLIN study [17], when brolucizumab treatment was administered at 4-week intervals, there was an increased incidence of IOI, resulting in the termination of the study. This result represents a previously unidentified aspect not discernible in the original clinical trials.

Faricimab is a more recently introduced anti-VEGF agent. In the TENAYA and LUCERNE studies, the incidence of IOI was 3.0% in patients treated with faricimab, and these values were not significantly different from those reported in patients treated with aflibercept [3]. Generally, faricimab showed a good safety profile in real-world practice. The incidence of IOI ranged from 0.5% to 1.6% [18,19], and no serious inflammatory complication, such as retinal arterial occlusion or occlusive vasculitis, was reported. With more extended patient follow-up data, we may better elucidate the associated of IOI with the agent.

As the patents for existing anti-VEGF drugs have expired, biosimilars are actively being developed and introduced. Biosimilars demonstrate efficacy equivalent to those of existing drugs but may not be 100% identical in nature. Clinical trials for the introduction of biosimilars have reported adverse events that were not significantly different from those of the original drugs [20]. However, similar to clinical trials for new drug development, these trials for biosimilar drugs also have limitations in that they included limited numbers of patients. The safety of these medications remains a concern among healthcare professionals [21]. Timtim et al. mentioned that, due to quality control issues in an early biosimilar product, the incidence of IOI reached as high as 10% [22]. Since most anti-VEGF biosimilar products have been introduced recently, the real-world safety of biosimilars will require close monitoring in the future.

3. Conclusion

Safety is a critical issue for patients with neovascular AMD. Although clinical trials provide key information regarding drug safety, they may not fully reflect real-world scenarios. Thus, it is important to bear in mind that potential safety issues that are not considered major concerns in clinical trials can have implications in real-world clinical settings, especially when utilizing newly introduced anti-VEGF agents.

4. Expert opinion

Critical safety issues associated with investigational drugs can be assessed through clinical trials. Certain drugs, such as abicipar pegol, did not receive approval due to significant safety issues that arise during clinical trials. However, because clinical trials are conducted on a limited number of patients, accurately identifying the incidence of rare complications and their associated risk factors can be challenging. Furthermore, it is important to consider that the safety of patients who do not meet the eligibility criteria for clinical trials cannot be determined based on trial results.

With recent efforts to develop drugs with longer duration of action, the design of clinical trials has become more complicated. Such designs employ exclusion criteria that encompass a wider range and involve fewer administrations of the investigational drug compared with prior studies [3]. Therefore, in the future, understanding these complex clinical trial designs will be necessary to identify safety issues that are difficult to evaluate through trials and to ensure the safe introduction of new drugs. Particularly, the reduced injection frequency of the investigational drug may underestimate drug-related adverse events.

Declaration of interests

J.H. Kim received lecture fees from Novartis Korea, Bayer Korea, and Roche Korea. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are a consultant for Bayer, Revana, Alkahest and provided research support for Alexion, Abbvie. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.