Scientists warn of unforeseen risks associated with an antibody drug approved in more than 70 countries for age-related macular degeneration.

According to recent studies, a monoclonal antibody drug known as brolucizumab, approved for the treatment of wet age-related macular degeneration (AMD) in 2019, may have rare side effects due to its interaction with the human immune system.

AMD is a debilitating eye condition prevalent in people aged 65 and above, which results in vision loss due to abnormal blood vessel growth in the macula of the eye. Brolucizumab was designed to counteract this overgrowth.

However, a small percentage of patients experienced uncommon retinal side effects soon after starting the drug. Researchers at Novartis AG, the Swiss pharmaceutical company that developed the drug, investigated this phenomenon in two new studies, seeking to understand the underlying reasons for these adverse reactions.

Although brolucizumab has been approved for use in over 70 countries and passed pre-approval safety testing, reports began to surface shortly after its launch regarding rare retinal disorders in a small subset of patients. According to data published in Science Translational Medicine, approximately 2.1% of patients treated with the drug experienced these side effects.

In response, Novartis AG conducted investigations at two research centers, one located in Basel, Switzerland and the other in Cambridge, Massachusetts. Scientists in both centers aimed to uncover the reason why brolucizumab was linked to retinal side effects in some patients while the majority remained unaffected. One study examined serum samples, while the other utilized models of the inflammatory conditions experienced by patients.

Vascular endothelial growth factor-A (VEGF-A) is a signaling protein that has various functions, including promoting the growth of abnormal blood vessels. In wet age-related macular degeneration (AMD), these abnormal blood vessels grow in the choroid layer of the eye, located beneath the light-sensitive retina, leading to vision loss.

Anette C. Karle, the lead author of one of the new studies, wrote in Science Translational Medicine that patients who experienced negative effects from brolucizumab developed specific eye conditions. Karle noted that rare cases of retinal vasculitis and/or retinal vascular occlusion were reported in 2020, often within the first few months after starting treatment, indicating a potential immunologic pathobiology.

Retinal vasculitis is an inflammatory condition that affects the blood vessels of the retina, the light-sensitive tissue located at the back of the eye. One of the most insidious aspects of retinal vasculitis is the painless loss of vision it causes. On the other hand, retinal vascular occlusion occurs when there is a blockage in the veins that carry blood away from the retina, which can lead to fluid retention or edema in the macula. This accumulation of fluid occurs not only within the retina but also beneath it, resulting in rapid and severe loss of visual acuity.

According to research conducted by Karle and her colleagues, the retinal disorders observed in patients were “inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, retinal vasculitis or retinal occlusion, despite the presence of preexisting and treatment-emergent antidrug antibodies in some [test] animals.” Nevertheless, a small group of patients in the clinical trial experienced both inflammatory conditions after being treated with brolucizumab.

To determine why brolucizumab was ineffective for some patients, Karle and her colleagues compared serum samples from various groups, including nonhuman primates, untreated healthy volunteers, and 28 patients from clinical trials who had experienced retinal vasculitis or retinal vascular occlusion following brolucizumab treatment.

Their analysis of serum samples revealed that an immune response against brolucizumab was a prerequisite for both side effects, as only patients with retinal vasculitis or retinal vascular occlusion exhibited strong T cell responses to the treatment. In essence, the patients’ immune systems were attacking their retinas after receiving the drug.

In a second study, which was also reported in Science Translational Medicine, Dr. Jeffrey Kearns and his team used a translational approach to investigate how the body can trigger inflammatory responses following brolucizumab treatment.

They employed various techniques such as structural modeling and immunological analysis to investigate the underlying causes of retinal vasculitis and retinal vascular occlusion.

The initial hypothesis was that the presence of antidrug antibodies in these patients suggested that immune complexes could play a critical role. However, Kearns noted that while the formation of antidrug antibodies and immune complexes could be a prerequisite, there are likely other factors at play, as only some patients develop retinal vasculitis or retinal vascular occlusion while the majority do not.

In their investigation of brolucizumab’s impact, Kearns and his team utilized a systems pharmacology model that simulated the eye’s conditions. This approach enabled the researchers to identify various elements that influenced how the treatment interacted with immune cells. Specifically, they discovered a linear epitope on the drug that was comparable to proteins found in gut bacteria, as well as non-native derivatives of brolucizumab that emerged after 13 weeks. These occurrences resulted in the creation of immune complexes between brolucizumab and anti-drug antibodies.

Karle and Kearns, along with their collaborators, emphasize that further research is necessary to obtain more conclusive findings. Both scientists highlight that there could be other unknown variables at play since their experiments were restricted by the scarcity of intraocular clinical samples and a deficiency of genetic risk factors.

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