Author: Robert Schmouder (United States)
Co-authors: Benjamin Maciejewski, Anette Karle, James Glick, Tina Rubic-Schneider, David Ledieu, Jen Watts
There have been recent, multiple, post-marketing case reports linking Beovu (brolucizumab) treatment with the findings of retinal vasculitis (RV) and/or retinal vascular occlusion (RO). These findings are typically in the presence of intraocular inflammation and have led to an update of the Beovu prescribing information. The reported cases predominantly occurred in the first several months after treatment initiation; a time of onset consistent with a possible immunologic mechanism. The purpose of the current study was to determine if patients similar to those in the case reports manifested evidence of a systemic immune response directed against brolucizumab.
BASICHR0049, a non-interventional study, collected at-home blood samples from patients in the USA who had received marketed Beovu.
From June to August 2020, blood (sera, plasma, peripheral blood mononuclear cells [PBMCs]) was collected from 11 patients treated with Beovu. Five of these patients had an RV/RO event while on Beovu and were no longer receiving Beovu at the time of blood collection. Six patients were receiving Beovu treatment and had not had an RV/RO event; they were considered controls. Blood was assayed for isotyping and titer determination of anti-drug antibodies (ADAs) against brolucizumab, in vitro T cell proliferation response to brolucizumab, and in vitro whole blood impedance platelet aggregometry.
The RV/RO cases had a higher range of total ADA titer (1004 – 50950) compared to controls (200 – 790) and a higher frequency of neutralizing ADAs compared to controls (80% vs 0%, respectively). The ADAs measured were predominantly IgG isotype and IgG1 and IgG3 subclasses in both cases and controls. Upon in vitro stimulation with brolucizumab, PBMCs from RV/RO cases had a 1.3- to 1.5-fold increase (p=0.03) in total CD4 T cell activation and a 1.4- to 1.7-fold increase (p=0.11) in memory CD4 T cell activation compared to controls. When patient plasma was incubated in the presence of healthy volunteer whole blood and supraphysiologic concentrations of brolucizumab and VEGF-A, platelet aggregation was increased 2.9-fold (p<0.023) in RV/RO cases compared to controls.
Even in the setting of the COVID-19 pandemic, it was possible to obtain at-home collected blood from Beovu-treated nAMD patients. Beovu-associated RV/RO was characterized as a systemic, drug-specific, mature B cell and T cell mediated immune response that included downstream in vitro platelet aggregation.
Employee, Novartis Institutes of BioMedical Research, Cambridge, MA, USA
Co-author: 7. Dominique Brees - Novartis Institutes of BioMedical Research, Basel, Switzerland; Novartis Pharma AG, Basel, Switzerland