Severe Intraocular Inflammation Following Intravitreal Faricimab

Key Points

Question

What were outcomes after 3 cases of acute, severe intraocular inflammation (IOI) within 1 month at 3 locations within 1 institution following intravitreal injection of faricimab for neovascular age-related macular degeneration?

Findings

In this case series, within 1 month at a single institution (19 retina specialists), 3 cases of acute, severe IOI were noted following injection of faricimab (2 different lot numbers at 3 locations). Findings of initial vitreous taps were negative in all cases; 1 subsequent intraoperative tap was positive for Staphylococcus epidermidis.

Meaning

These observations support the need for continued vigilance for acute, severe IOI following intravitreal faricimab.

This case series describes 3 initially culture-negative cases of acute, severe, posterior-segment intraocular inflammation events occurring within the same month following faricimab intravitreal injections at a single institution.

Abstract

Importance

Monitoring for and reporting potential cases of intraocular inflammation (IOI) in clinical practice despite limited occurrences in clinical trials, including experiences with relatively new intravitreal agents, such as brolucizumab, pegcetacoplan, or faricimab, helps balance potential benefits and risks of these agents.

Objective

To provide descriptions of 3 initially culture-negative cases of acute, severe, posterior-segment IOI events occurring within the same month following intravitreal faricimab injections at a single institution.

Design, Setting, and Participants

In this case series, 3 patients manifesting acute, severe IOI following intravitreal injection of faricimab were identified between September 20, 2023, and October 20, 2023.

Exposure

Faricimab, 6 mg (0.05 mL of 120 mg/mL solution), for neovascular age-related macular degeneration among patients previously treated with aflibercept; 1 patient also had prior exposure to bevacizumab.

Main Outcomes and Measures

Visual acuity, vitreous taps for bacterial or fungal cultures, and retinal imaging.

Results

All 3 patients received intravitreal faricimab injections between September 20 and October 20, 2023, from 2 different lot numbers (expiration dates, July 2025) at 3 locations of 1 institution among 3 of 19 retina physicians. Visual acuities with correction were 20/63 OS for patient 1, 20/40 OD for patient 2, and 20/20 OS for patient 3 prior to injection. All 3 patients developed acute, severe inflammation involving the anterior and posterior segment within 3 to 4 days after injection, with visual acuities of hand motion OS, counting fingers OD, and hand motion OS, respectively. Two patients were continuing faricimab treatment while 1 patient was initiating faricimab treatment. All received intravitreal ceftazidime, 2.2 mg/0.1 mL, and vancomycin, 1 mg/0.1 mL, immediately following vitreous taps. All vitreous tap culture results were negative. One patient underwent vitrectomy 1 day following presentation. Intraoperative vitreous culture grew 1 colony of Staphylococcus epidermidis, judged a likely contaminant by infectious disease specialists. All symptoms resolved within 1 month; visual acuities with correction were 20/100 OS for patient 1, 20/50 OD for patient 2, and 20/30 OS for patient 3.

Conclusions and Relevance

In this case series, 3 patients with acute, severe IOI within 1 month at 3 different locations among 3 ophthalmologists of 1 institution following intravitreal faricimab could represent some unknown storage or handling problem. However, this cluster suggests the continued need for vigilance to detect and report such cases following regulatory approval.

Introduction

Faricimab (Vabysmo; Genentech) was designed to be a combined-mechanism biologic agent, with simultaneous effects on vascular endothelial growth factor A (VEGF-A) and angiopoietin 2. Approval for treatment of diabetic macular edema, neovascular (wet) age-related macular degeneration (AMD), and macular edema associated with retinal vein occlusion by the US Food and Drug Administration (FDA) followed numerous randomized clinical trial results.^1,2,3 A recent Health Care Provider Letter,⁴ dated November 2023, provided an update to the Warnings and Precautions and Adverse Reactions—Postmarketing Experience sections of faricimab’s US Prescribing Information. The letter implied “spontaneous post-marketing reports of retinal vasculitis with or without occlusion in patients treated with VABYSMO”⁴ were relatively rare. Specifically, “As of the end of August 2023, with 1.5 million vials dosed globally, the estimated reporting rate of retinal vasculitis with occlusion is 0.06/10,000 injections (for retinal vasculitis with or without occlusion: 0.17/10,000 injections).”⁴ Revisions to the US Prescribing Information⁵ recommended discontinuing faricimab in patients who developed these events. Potentially related to these presumably rare intraocular inflammation (IOI) events, we recognized 3 cases of acute, severe IOI occurring within the same month at 3 different locations of our institution among 3 ophthalmologists (S. B. B., M. S., and A. S. W.). These events seemed unlikely to be coincidental, leading to the genesis of this case series report. We are unaware of similar events in the peer-reviewed medical literature with faricimab at this time. While it is possible this cluster was due to some unknown handling or storage problem, these events are brought to the attention of other ophthalmologists using faricimab in case such occurrences are more frequent than previous publications of clinical trials have suggested.

Methods

At a single institution (Retina Division of the Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Mayland) with 3 clinic locations, 3 patients presented with acute, severe, presumably sterile IOI events several days after receiving injections of intravitreal faricimab, 6 mg (0.05 mL of 120 mg/mL solution), between September 20, 2023, and October 20, 2023. All patients were receiving treatment for neovascular AMD with the following faricimab lot numbers: patient 1 received National Drug Code 50242-096-01, lot B1510B11; patient 2, National Drug Code 50242-096-01, lot B1507B15; and patient 3, National Drug Code 50242-096-01, lot B1510B11. No handling or storage problems were noted. The cluster of cases were reported promptly to the Department of Ophthalmology’s Vice Chair for Quality and Safety. The intravitreal procedures were performed in a room dedicated to intravitreal injections under aseptic conditions. Three retina physicians (S. B. B., M. S., and A. S. W.) at 3 different clinic locations (Johns Hopkins Hospital and 2 satellite locations) followed similar injection procedures after receiving written informed consent. A metal eyelid speculum was used in all cases. Eyes were prepped with several applications of proparacaine, 0.5%, and included povidone-iodine, 5% (Betadine), directly to the injection site and left in place for at least 30 seconds prior to injection. Intravitreal injections were administered with 30-gauge needles. Eyes were rinsed with balanced salt solution or any external povidone-iodine was wiped off following the procedure. No postinjection topical antibiotics were given. Numbers of total faricimab injections and total anti-VEGF intravitreal injections other than faricimab that were administered by the 19 Retina Division physicians at Johns Hopkins Hospital and all satellite locations were obtained from billing records from September 20, 2023, through October 20, 2023. The billing records were reviewed for quality assurance purposes and then used to calculate the percentage of cases that these IOI events represented among all anti-VEGF injections within the Retina Division.

This case series follows reporting guidelines for uncontrolled case series.⁶ Research was conducted in accordance with regulations set forth by the Health Insurance Portability and Accountability Act. All protected health information was deidentified. Based on principles outlined in the Declaration of Helsinki, all authors judged the investigation was excluded or exempt from institutional review board approval as permitted by the Johns Hopkins University School of Medicine Institutional Review Board policies⁷ because only deidentified data were used in the study and no more than 3 cases were included.

Results

From September 20, 2023, through October 20, 2023, 3 retina physicians (S. B. B., M. S., and A. S. W.) in the Retina Division of the Department of Ophthalmology at Johns Hopkins University School of Medicine each had a patient develop acute, severe, presumably sterile IOI following intravitreal injection of faricimab from 2 different lot numbers at 3 different clinic locations. The cluster of events was judged unlikely to be coincidental or from some unknown handling or storage issue. Recent reports of retinal vasculitis following faricimab prompted further evaluation, for quality assurance purposes, to evaluate these cases systematically. There were 182 injections of faricimab, including these 3 cases (1.6%), and 1223 injections of all other anti-VEGF agents (including aflibercept, repackaged [compounded] bevacizumab, and ranibizumab) administered by Retina Division physicians during this time interval. No other cases of acute, severe IOI, including no other cases of infectious or noninfectious endophthalmitis following any other intravitreal anti-VEGF injections, were reported among these 19 physicians. Using the Rule of Three,⁸ there was at least 95% confidence that the true rate of at least 1 acute, severe IOI event after using a nonfaricimab drug within a month was less than 3 in 1253 (0.24%; ie, less than 1 in 400). The 3 cases are detailed below.

Case 1

A man aged 76 years had a medical history of hypertension, benign prostate hyperplasia, and hyperlipidemia. His ocular history included cataract surgery in each eye in 2014 and anti-VEGF treatment for neovascular AMD, first with repackaged (compounded) bevacizumab, then aflibercept, 2 mg, and subsequently faricimab. At his visit immediately preceding his 15th faricimab injection in his left eye for neovascular AMD, visual acuity (VA) with correction was 20/63 OS on an Early Treatment Diabetic Retinopathy Study chart. Three days later, he presented with moderate, throbbing pain and decreased vision in his left eye. VA was hand motion OS; intraocular pressure (IOP) was 15 mm Hg. He had periorbital swelling, tenderness of eyelids to palpation, diffuse conjunctival erythema, and diffuse corneal stromal edema. The anterior chamber (AC) had cells and a 0.5-mm layering hypopyon. Posteriorly, there was dense vitreous debris obscuring the ability to determine if there was a retinal detachment (Figure 1A). Ultrasonography showed vitritis but no retinal detachment (Figure 1B). A vitreous tap was sent for bacterial and fungal cultures but not polymerase chain reaction (PCR) analyses. Immediately thereafter, intravitreal ceftazidime, 2 mg, and vancomycin, 1 mg, were injected. Findings of vitreous cultures were negative for bacterial or fungal organisms. He started hourly topical prednisolone drops 1 day after his IOI presentation. His pain rapidly improved. The hypopyon resolved in 7 days. VA improved to counting fingers OS by 2 weeks after presentation. The vitritis gradually resolved. The retinal periphery could be viewed at 14 days (Figure 1C). Approximately 6 weeks following his presentation, his VA with correction improved to 20/100 OS. All AC inflammation resolved. Serial optical coherence tomography images showed development of macular epiretinal membranes with progressive macular traction and recurrence of interstitial fluid (Figure 1D), presumably from neovascular AMD or associated with the macular traction or both. Clinical examination did not suggest any retinal vasculitis. Aflibercept, 2 mg, was resumed as needed with no subsequent inflammatory events.

Figure 1. Timeline of Patient 1 From Presentation to Resolution of Inflammation.

A, Ultra-widefield fundus image of patient 1 shows vitreous debris and intraretinal hemorrhages on presentation with vitreous opacities. B, No retinal detachment was noted on B-scan ultrasonography when visual acuity with correction had decreased from 20/63 OS at his visit immediately preceding his last intravitreal injection to hand motion OS at this visit. C, Two weeks after receiving faricimab and treatment for vitritis, there was marked reduction of vitreous debris with an improved view of the retina. D, Six weeks following his presentation with vitritis, visual acuity with correction improved to 20/100 OS associated with development of macular epiretinal membranes with progressive macular traction as well as recurrence of interstitial fluid on optical coherence tomography, potentially from his neovascular age-related macular degeneration or an effect of the macular traction or both.

Case 2

A man aged 73 years had an ocular history in the right eye of radial keratotomy in his 20s, a chorioretinal scar of unknown etiology inferior to the fovea noted since his initial presentation in 2018, a macular hole repair in 2018, and cataract surgery in 2019. His medical history included hypertension and first-degree atrioventricular block. His VA with correction was 20/40 OD on a Snellen chart immediately preceding his 10th faricimab injection given for choroidal neovascularization with polypoidal choroidal vasculopathy, which was previously treated with aflibercept. Three days following this injection, he had mild pain and decreased vision in his right eye. The VA decreased to counting fingers OD; IOP was 13 mm Hg. He had corneal stromal edema, AC cells, and a 0.8-mm layering hypopyon. He had dense vitreous cells and no view of the retina. B-scan ultrasonography showed vitritis with no retinal detachment. A vitreous tap was sent for bacterial and fungal cultures, but not PCR analyses, immediately followed by intravitreal injections of ceftazidime, 2 mg, and vancomycin, 1 mg. The patient also started topical prednisolone drops 4 times a day and monitored closely. Vitreous cultures did not grow any bacterial or fungal organisms. Twelve days after his presentation, his hypopyon resolved. VA with correction improved to 20/60 OD on a Snellen chart. One month later, VA with correction improved to 20/50 OD. AC and vitreous inflammation resolved. Scattered intraretinal hemorrhages were noted with no vascular sheathing. Because of persistent subretinal fluid, he received aflibercept, 2 mg, with no subsequent inflammation.

Case 3

A woman aged 78 years had an ocular history of cataract surgery in each eye in 2018. She had received numerous aflibercept injections for neovascular AMD previously in her left eye. VA with correction was 20/20 OS on a Snellen chart immediately preceding her first faricimab injection. She presented with throbbing pain, photosensitivity, and decreased vision in the left eye 4 days later. VA was hand motion OS; IOP was 13 mm Hg. Slitlamp examination showed a 1-mm hypopyon. There were vitreous cells and scattered intraretinal hemorrhages. Because the view of the retinal periphery was compromised, a B-scan ultrasound was performed, confirming absence of a retinal detachment. Vitreous tap and AC samples were sent for bacterial and fungal cultures, but not PCR analyses. Immediately thereafter, intravitreal injections of ceftazidime, 2 mg, and vancomycin, 1 mg, were administered. The next day, given persistent throbbing pain, photosensitivity, and lack of clinical improvement, the patient underwent 23-gauge vitrectomy with AC washout and repeated injection of intravitreal ceftazidime, 2.2 mg, and vancomycin, 1.0 mg, in the operating room. Undiluted vitreous and AC fibrin samples were sent for additional bacterial and fungal cultures. On postoperative day 1, the patient had substantial reduction in pain. AC inflammation had improved substantially, and there was minimal vitreous cavity debris. The optical coherence tomography from postoperative day 2 showed a clear vitreous cavity with a pigment epithelial detachment (Figure 2A), similar to what was noted 1 month previously. Findings of the initial clinic-obtained cultures remained negative. However, subsequent intraoperative cultures grew 1 colony of Staphylococcus epidermidis. This minimal growth was judged likely to be a contaminant following review with a professor in the Division of Infectious Diseases at Johns Hopkins University School of Medicine with experience and expertise in the interpretation of these cultures (Khalil Ghanem, MD, PhD). The judgment that the findings were typical for contamination was based on the following circumstances: (1) the culture included only a single bacterial colony from a site with severe inflammation; (2) there was no bacterial growth from cultures of the vitreous tap on the previous day; and (3) if this pathogen were causing the inflammation, the culture should have grown the organism more abundantly.

Figure 2. Optical Coherence Tomography Abnormalities in Patient 3 .

A, Optical coherence tomography of patient 3 on postoperative day 2 following vitrectomy with anterior chamber washout and repeated intravitreal injection of antibiotics showed clearing of vitreous cavity debris with a pigment epithelial detachment similar to what was noted 1 month previously. B, Three weeks after presenting with vitritis and following resolution of inflammation, optical coherence tomography showed recurrence of subretinal fluid associated with neovascular age-related macular degeneration.

The patient was given topical prednisolone drops. Three weeks later, VA with correction improved to 20/30 OS on a Snellen chart, and there was complete resolution of inflammation. Because of recurrence of subretinal fluid from her neovascular AMD, intravitreal aflibercept was given, with no inflammation 1 month later (Figure 2B).

Discussion

Acute, severe, sterile IOI after intravitreal injections have been reported with many commonly used anti-VEGF agents, including aflibercept⁹ and ranibizumab.¹⁰ More recently, this type of IOI as well as relatively rare reports of acute severe IOI associated with occlusive retinal vasculitis have been reported with more recently approved intravitreal agents for retinal diseases, including brolucizumab,¹¹ pegcetacoplan,¹² and faricimab^1,2,3 as well as biosimilar agents ranibizumab¹³ and aflibercept.¹⁴ Nevertheless, these clinical trial reports, including those for faricimab, have reported infrequent severe IOI events.^{1,2,3,9,10,11,12,13,14,15} Inflammatory complications following intravitreal anti-VEGF injections that are sterile are characterized by acute-onset IOI without infection that resolve without antibiotic treatment.¹⁵ The reported incidence for aflibercept, bevacizumab, or ranibizumab has varied from 0.02% to 0.37%. Presentation usually occurs between 1 and 7 days after injection.¹⁵ However, it seems unlikely that 3 severe, acute, presumably noninfectious IOI events were noted coincidentally within the same month by 3 different retina physicians at 3 different clinic locations within a single institution following intravitreal faricimab from 2 different lot numbers.

These relatively frequent IOI events (1.6% of all faricimab injections) within a 1-month time frame at a single institution may be different from the retinal occlusive IOI events with faricimab that prompted Genentech’s Letter to Health Care Providers,⁴ which indicated new warnings and precautions regarding retinal vasculitis and/or retinal vascular occlusion following intravitreal injection of faricimab.⁵ Specifically, none of the patients in this current case series had signs of retinal arteritis or venulitis once the ocular media cleared. Their frequency, though, supports the possibility that rates of acute, severe IOI in clinical trials following faricimab^1,2,3 might not accurately capture the clinical practice setting expectations of these events. The relatively small number of cases in this series precludes determining with confidence the true incidence of this complication at this time.

There have been at least 2 types of sterile inflammation reported following intravitreal injections. One is an acute onset of sterile inflammation as seen in the patients in our series. It presents within the first 5 days of injection, and patients present with decreased VA, AC cell, variable levels of ocular pain, and vitreous cells or other vitreous debris.¹² It is often difficult to distinguish this presentation from infectious endophthalmitis; however, most patients return to baseline VA. The other is a delayed onset inflammation that has been noted with and without retinal vasculitis, for example, as reported with brolucizumab,¹¹ and perhaps similar to the more recently described occlusive retinal vasculitis events following pegcetacoplan or faricimab. Predominant symptoms typically include floaters, sometimes approximately 14 days after injection. Clinical findings sometimes include only a few cells in the AC with keratic precipitates. In several cases of IOI associated with brolucizumab, a relatively specific phenotype showing occlusive arteritis with fluorescein leakage not at branch arterioles was noted. While fluorescein angiography was not obtained in this case series of inflammation following faricimab, ophthalmoscopy and review of ultra-widefield retinal images specifically did not show focal areas of inflammation along arterioles.

There are several postulated mechanisms for sterile IOI following intravitreal injections.¹⁶ One mechanism includes patient susceptibility. Some patients may have treatment-induced or treatment-boosted antidrug antibodies (ADA) that may be associated with subsequent inflammation. Rates of ADA were approximately 44% for brolucizumab, which could be contributing to the increased IOI following its administration.¹¹ However, some of these ADA assays can be positive presumably from cross-reactivity to something unrelated to anti-VEGF agents that exists in an individual prior to administration of an intravitreal anti-VEGF agent. Second, the manufacturing process of the biologic agent can elicit an inflammatory reaction. For example, protein aggregates of the drug might induce silicone oil release from syringes, and this might incite an inflammatory reaction.¹⁷ Third, the properties of the agent itself might elicit an inflammatory response. One potential explanation for this occurrence is an inflammatory reaction triggered by the fragment crystallizable antibody portion present on aflibercept and bevacizumab, which is absent on the ranibizumab molecule. This was used during the development of faricimab, which is bound by a modified fragment crystallizable region that eliminates binding of fragment crystallizable γ receptor and neonatal fragment crystallizable receptors, potentially decreasing both inflammation and systemic exposure.¹⁸ However, our case series suggest this theoretical advantage might not necessarily translate into decreased IOI in the clinical practice setting.

Limitations

Limitations of this case series include the potential for selection bias of what could be a coincidence of rare cases of IOI following faricimab that had been reported previously. Nevertheless, the chance of such a coincidence seems low, warranting consideration that this cluster of cases within 1 month may represent more than just a coincidence of rare cases. Another limitation is the possibility that all 3 cases were infections endophthalmitis in the setting of negative cultures with resolution as a result of intravitreal antibiotics. This possibility seemed less likely given the unlikelihood of having 3 cases of infectious endophthalmitis in 1 month, all with negative culture findings following a vitreous tap, although 1 case had growth of a likely contaminant. At our institution, 13 of 17 cases of severe IOI (75%), including endophthalmitis, over a 7-year period had positive culture findings.¹⁹ Furthermore, there was only mild to moderate pain in these 3 cases following faricimab, and all resolved promptly with VAs approaching that noted prior to the IOI events. Also, the retrospective design precludes determining if there was a breach in proper handling or storage of the faricimab prior to or after delivery to 3 different clinics. However, this seems unlikely when the events occurred among 3 different clinic locations with 2 different lot numbers, and we are unaware of any breach of these procedures.

Conclusions

In conclusion, 3 sporadic, acute, severe IOI reactions within a 1-month time frame were noted in patients who received faricimab at 3 different clinics from 1 retina practice. The absolute infrequent number of cases limits confidence in this hypothesis, and an unknown handling or storage problem cannot be ruled out. Anti-VEGF agents have positively transformed the management and prognosis of many common and uncommon retinal diseases. Nevertheless, acute severe IOI events such as this case series emphasize the need for continued vigilance to detect and report such cases to appropriate groups, as was done in these cases to the Food and Drug Administration and the American Society of Retina Specialists. The severity and frequency of these relatively rare events from the clinical practice setting, in case series or determined, for example, from large registries or insurance databases, then can be weighed when balancing the risks and benefits of choosing anti-VEGF agents to treat retinal diseases.

Supplement.

Data Sharing Statement