The evolving story of vasculitis and occlusive vasculitis associated with brolucizumab (Beovu; Novartis) has piqued the interest of many retina specialists around the world. Many questions arise after the release of a recent safety analysis report from an independent ASRS review committee, which characterized the vasculitic events and likelihood of vision loss associated with these events. What steps will Novartis take to identify the cause of these vasculitic events? How does Novartis move forward with brolucizumab in its current form? What happens to clinical trials that were enrolling and ongoing? How do we, as a retina community, evaluate brolucizumab and does this still play a role in the anti-VEGF armamentarium? We were fortunate enough to virtually sit down with Charles Wykoff, MD, and Novartis Chief Medical Officer Marcia Kayath, MD, to ask these difficult, but essential, questions.

Yasha Modi, MD: Novartis has launched a very thoughtful committee that you are a part of to conduct root cause analysis with the hopes of lowering these events. What is the thought process on how to address this at a practical level? What is the scope of this analysis? Will the analysis apply just to the phase 3 patients or those in the post marketing data as well?

Charles C. Wykoff, MD, PhD: Novartis has established a dedicated internal team that is collaborating with a large group of global experts spanning multiple disciplines including retina, immunology, and manufacturing to examine root causes, risk factors, mitigation strategies, and treatment protocols for the adverse events of intraocular inflammation and occlusive vasculitis that have been associated with the use of brolucizumab. This global coalition is using an array of innovative collaborative approaches, including crowdsourcing communities to generate and thoroughly investigate a broad range of hypotheses for the underlying cause(s) of these adverse events. The entire team is expressly committed to transparently communicating all facts and findings to the entire ophthalmic community to ensure that retina specialists have the data and understanding needed to appropriately manage their patients.

Dr. Modi: Regarding the clinical trials that are ongoing with Beovu, what would be the advice of the committee members when considering enrollment?

Dr. Wykoff: Currently, I am not aware of any prospective trials using brolucizumab that are actively enrolling new patients. There are multiple studies that are fully enrolled, such as MERLIN (NCT03710564) and KESTREL (NCT03481634), and patients are within the active phase of these studies. Other studies have been put on hold.

For patients enrolled in clinical trials, before injecting, physicians are encouraged to look for signs of intraocular inflammation, which may include examination by slit lamp and posterior-segment imaging. If active intraocular inflammation is present, it is recommended that any intraocular injection of study medication not be administered, and the intraocular inflammation should be managed as indicated. Patients should be reminded to contact their physician immediately if they notice any changes in vision or any signs of inflammation, such as eye pain, floaters, discomfort, or redness.

Dr. Modi: Which AMD patients are viable candidates for Beovu usage given the current safety signals?

Dr. Wykoff: Fortunately, the field has had access to excellent anti-VEGF pharmaceuticals in aflibercept, bevacizumab, and ranibizumab. These agents have been used, mostly without substantial concern for safety, for many years. The value that we as a field hoped to realize with brolucizumab was a more effective drying agent that may allow for less frequent dosing in clinical practice. The HAWK and HARRIER phase 3 data sets provided evidence for the capacity to highly effectively dry the retina, and practitioners were excited to use this clinically. Unfortunately, the safety concerns that have surfaced related to intraocular inflammation and occlusive vasculitis have made incorporating this pharmaceutical into routine clinical practice very challenging. If physicians do use this medication outside of a clinical trial, it is important that the patient be made aware of the possibility for these safety events and that a comprehensive eye examination be considered at each clinical visit to evaluate for any signs of inflammation.

Dr. Modi: For the root cause analysis, how does Novartis and the scientific team address the molecular properties of Beovu and systematically test them to understand what specific aspect may be contributing to these occlusive vasculitic events?

Marcia Kayath, MD: We are committed to continuing to collaborate with the scientific and broader retina community to better understand the root causes and potential risk factors associated with these rare adverse events. It is important to note that Novartis has assembled a fully dedicated internal team to collaborate with top global experts to examine 4 key questions regarding adverse events associated with Beovu:

• What are the root causes of these events?
• Are there patients at higher risk and can we characterize them?
• What can be done to lower the incidence of these events?
• How should these events be treated?

This team is empowered to whiteboard any and all ideas as potential hypotheses. Once “on the board,” these hypotheses stay until they are either confirmed or disproved with data. We are dedicated to turning over every stone; looking carefully at vascular occlusion and inflammation pathogenesis, formulation, and patient characteristics; and enhancing our toxicology work with additional animal models. We are conducting these analyses and studies in our facilities around the world. We have learned a lot in just a few months and expect to finish many of our studies soon, as we would like to be able to share our findings with the community in the coming months.

Dr. Modi: Were there lower numbers of vasculitis events (based on the re-review of the adverse events) in the lower molar dose arms of Beovu in clinical trials? This may address the aspect of molar concentration and adverse events.

Dr. Kayath: Of the 50 cases of interest with intraocular inflammation with or without retinal vasculitis and/or retinal vascular occlusion, 17 had been treated with brolucizumab 3 mg and 33 with brolucizumab 6 mg. This proportion is in line with patient enrollment In HAWK and HARRIER, in which 358 patients were treated with brolucizumab 3 mg and 730 patients were treated with brolucizumab 6 mg. As there were no differences in severity, time of onset, and impact on visual acuity, there is no proof for a correlation of the events of interest with the molar concentration of the drug.

Before injecting, physicians are encouraged to look for signs of intraocular inflammation. If active intraocular inflammation is present, physicians must not perform an intraocular injection and should treat the intraocular inflammation according to medical practice. Instruct your patients to contact you immediately if they notice any changes in visual acuity or any signs of inflammation, such as eye pain, floaters, discomfort, or ocular hyperemia. As a reminder, Beovu is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, or known hypersensitivity to brolucizumab or any of the excipients.

Dr. Modi: Are there steps that Novartis is taking to consider reformulation of the drug and/or package in a prefilled syringe? If so, how does this get done and what is the potential timeline for this?

Dr. Kayath: We are looking at all potential factors, including formulation, patient characteristics, retinal vascular occlusion, and inflammation pathogenesis to explore the root cause. To date, there has been no identification of a correlation between a manufacturing issue, product quality, or prefilled syringe and retinal vasculitis and/or retinal vascular occlusion. We are honing in on a few leading hypotheses that we are vetting further. We are committed to reporting our findings to the retina community as soon as possible. RP