Recent research published in Science Translational Medicine on the Novartis AG-developed drug brolucizumab—for the treatment of wet age-related macular degeneration (AMD)—indicate it may cause rare retinal side effects due to interactions with the human immune system.
Talk about brolucizumab first.
Brolucizumab-dbll (Beovu) is a single-chain variable fragment molecule that targets vascular endothelial growth factor-A (VEGF-A) via an intravitreal injection to potentially slow the growth of abnormal blood vessels.
Approved by the FDA in 2019 for wet AMD (and in 2022 for diabetic macular edema [DME]), the drug is sold under the trade name Beovu. Recommended dosage is 6 mg a month for the first 3 months, followed by once every 2 to 3 months.
Now some background on these side effects.
Rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) following the first few months after initial treatment were first reported by the American Society of Retinal Specialists (ASRS) in 2020.
These findings were in contrast to preclinical data supporting no drug-related intraocular inflammation or RV/RO in non-human studies.
Tell me about this research.
Investigators from Novartis conducted two studies to research these reports and determine why such retinal side effects were occuring in some patients (an estimated 2.1%) treated with brolucizumab and not others.
The first study analyzed serum samples (taken from nonhuman primates, healthy untreated volunteers, and 28 patients who reported RV/RO side effects), while the second study used a translational approach (including structural modeling and immunological analysis) on the inflammatory conditions reported in the patient cases to determine the underlying causes of RV/RO.
Findings?
In the first study, only patients with reported RV/RO side effects exhibited strong T-cell responses to brolucizumab—indicating that an immune response against the drug was required for both side effects.
The second study identified brolucizumab’s effects on immune cells using a model that mirrored RV/RO conditions in the eye.
They found a linear epitope (binding spot on the antigen) of the drug similar to gut bacteria proteins and non-native derivatives of brolucizumab that developed after 13 weeks—leading to immune complexes between anti-drug antibodies and brolucizumab.
Any limitations?
The authors noted potential unknown variables in both studies, as each experiment was restricted by a lack of genetic risk factors and shortage of intraocular clinical samples.
What’s next?
Researchers in both studies advised that additional research is required before drawing any definitive conclusions on the retinal side effects following treatment with brolucizumab.