Biography: Singh is a staff surgeon at the Cole Eye Institute, Cleveland Clinic and Associate Professor of Ophthalmology at the Lerner College of Medicine in Cleveland Ohio. He also currently serves as the medical director of informatics at the Cleveland Clinic.
Disclosures: Singh reports he is a consultant to Novartis, Regeneron, Genentech, Gyroscope, Bausch + Lomb and Alcon and performs sponsored research for NGM and Apellis.
June 02, 2021
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BLOG: What’s next for Beovu?

Biography: Singh is a staff surgeon at the Cole Eye Institute, Cleveland Clinic and Associate Professor of Ophthalmology at the Lerner College of Medicine in Cleveland Ohio. He also currently serves as the medical director of informatics at the Cleveland Clinic.
Disclosures: Singh reports he is a consultant to Novartis, Regeneron, Genentech, Gyroscope, Bausch + Lomb and Alcon and performs sponsored research for NGM and Apellis.
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On the heels of the major announcement from Novartis that Beovu should not be used in intervals less than 8 weeks, some are wondering what the ultimate future of the drug will be.

In the most recent MERLIN study, the rates of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% for Beovu (brolucizumab) vs. 4.5% for Eylea (aflibercept, Regeneron). This was higher that the rates seen in the HAWK and HARRIER phase 3 clinical studies of around 4% with less frequent dosing than what was conducted in MERLIN. Thus, due to the increased rate seen with monthly dosing, in the interest of patient safety, Novartis recommended halting the two retinal vein occlusion studies RAPTOR and RAVEN along with the MERLIN study in which Beovu was given every 4 weeks for neovascular age-related macular degeneration. The retina community is appreciative of Novartis for their transparency in reporting these events.

Rishi P. Singh

While at face value some might call this an “overcall” in inflammation given that Eylea had never been previously reported to have a similarly high rate of inflammation reported ever in any trial, the rate of inflammation was real in the Beovu arm, resulting in more patients losing 15 letters of vision within the study. The two times higher rate of inflammation is simply not tolerable give the level of safety of currently available FDA-approved anti-VEGF agents with a reported IOI rate of less than 0.5%. And while clinicians agree that Beovu had the efficacy they hoped for in an anti-VEGF, the risk-reward benefit ratio is playing out in offices across the U.S.

So, what are the future possibilities for the drug? The first scenario would involve Novartis localizing the reason for the inflammation — a manufacturer impurity of some sort that it could eliminate from the system. A second scenario would identify a biomarker in the vitreous or serum so we can test patients ahead of time to make sure they would not have an IOI event. Thus far, it at least appears that patients with a history of uveitis and shortened intervals are at most risk, but this is not predictive enough, and antibodies to Beovu have not been positively linked to cases. A third scenario might be that there is just too much VEGF inhibition with Beovu and that normal vascular function depends on some circulating level of ambient VEGF to maintain normal homeostasis.

The retina community collectively looks forward to hearing more about the potential insights on the pathogenesis of the inflammatory issues surrounding Beovu.