Beovu offers model on how to handle unexpected complications
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Beovu, manufactured and distributed by Novartis, achieved FDA approval on Oct. 8, 2019.
FDA approval was based on two extensive prospective randomized masked clinical trials named HAWK and HARRIER. These clinical trials included more than 1,800 patients enrolled and followed for 96 months in 400 centers globally by the world’s top retina specialists.
Beovu (brolucizumab) is a lower molecular weight anti-VEGF molecule that allows a higher concentration of drug to reach the retina and choroid after an intravitreal injection. The HAWK and HARRIER studies confirmed the anticipated benefits vs. the predicate control Eylea (aflibercept, Regeneron): A greater subretinal and intraretinal fluid reduction, a more rapid and complete reduction in retinal thickness on OCT, drier retinas, and a potential reduction in injection frequency to quarterly after the first three monthly injections. The number of patients who improved 15 letters or lost five letters and the adverse event profile were equivalent to the predicate drug, Eylea, at 1 year. With 1,800 patients enrolled, adverse events as rare as 0.25% should have been evident.
Retina specialists and the marketplace expected rapid adoption of Beovu based on its efficacy profile with similar safety to the current market leader, Eylea. A meaningful shift in market share had occurred when Lucentis (ranibizumab, Genentech) was launched on top of Avastin (bevacizumab, Genentech) and when Eylea was launched on top of Lucentis. Unexpectedly, less than 1 year after FDA approval, early adopters of Beovu encountered intraocular inflammation, retinal vasculitis and vascular occlusion in a troubling number of patients.
Novartis appropriately and admirably instituted an intense and fully funded investigation through a Safety Review Committee, as did the American Society of Retina Specialists through its Research and Safety in Therapeutics Committee. These investigations revealed a 4.6% incidence of intraocular inflammation, a 3.3% incidence of retinal vasculitis and a 2.1% incidence of vascular occlusion 6 to 24 months after initiating Beovu injection, with the latter two capable of causing severe visual loss. These investigations continue, and the information gathered is being shared with the ophthalmic community with full transparency.
At this time, Beovu is still available to patients, but it has been relegated to secondary therapy. All drugs and devices are associated with both risks and benefits, and some expert retina specialists in collaboration with a fully informed patient are still finding Beovu a useful drug for select eyes unresponsive to other anti-VEGF drugs.
I believe the finding of unexpected risks with Beovu intravitreal injection for a sight-threatening disease, neovascular age-related macular degeneration, has been well managed by the retina community, ASRS, Novartis and the FDA. As an anterior segment surgeon, I cannot help but compare the Beovu product management to that of the Alcon CyPass micro-stent, which is now off the market after a Class I FDA recall. The CyPass micro-stent COMPASS-XT FDA post-approval study revealed an unexpected endothelial loss of 27.2% in 44 of 162 patients at 5 years after surgery. A similar investigation by expert glaucoma surgeons and the American Glaucoma Society revealed that this was most likely related to intermittent touch of the CyPass micro-stent’s proximal intracameral plastic to the corneal endothelium.
The CyPass device has multiple rings to stabilize it and prevent migration after implantation. Careful gonioscopy of 154 of the 162 patients in the study revealed that if zero rings were visible, endothelial cell loss was only 3.1% at 5 years, which is consistent with normal physiologic loss with age. If one ring was visible, cell loss was 8.4%, with two rings visible, 21%, and with three rings visible, 31.4%. This finding led many glaucoma experts to conclude that proper full implantation of the CyPass micro-shunt would minimize the risk for endothelial loss. In addition, those patients who demonstrated endothelial loss greater than physiologic on serial specular microscopy could have their micro-shunts trimmed or removed before corneal decompensation occurred.
Glaucoma, like neovascular AMD, is a potentially blinding disease, and alternative therapies, including trabeculectomy and tube shunt surgery, have many severe and sight-threatening complications, including accelerated endothelial cell loss. Finally, we have a safe and effective treatment for endothelial failure, an endothelial transplant. I have yet to find a master glaucoma surgeon, including my five glaucoma fellowship-trained partners, who does not want the CyPass micro-shunt back on the market and available to select patients with good informed consent, proper implantation and careful follow-up of the endothelium with serial specular microscopy.
The management of the unexpected complications associated with Beovu are, to me, a good model of how careful clinician observers amplified by their professional societies and an ethical manufacturer can work together with our regulatory bodies to manage a difficult situation. Perhaps a similar collaboration can bring back the CyPass micro-shunt to the benefit of thousands of glaucoma patients with difficult-to-treat disease.
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