Brolucizumab Hits Snag

RETINA CLINICAL UPDATE

t the beginning of this year, brolucizumab (Beovu) looked Alike it was set to follow a famil- iar pattern: A new anti-VEGF drug successfully navigates the long path to FDA approval, and ophthalmologists begin considering whether it can solve linger- ing clinical issues of treating age-related macular degeneration (AMD). But on Feb. 23, that scenario changed. In an alert to its members, the Ameri- can Society of Retina Specialists said that it had received reports of 14 cases of vasculitis following the drug’s approval on Oct. 7, 2019. Of these, 11 were designated by the reporting provider POTENTIAL BENEFIT. Two-year reduction in central subfield thickness in patients as occlusive retinal vasculitis.1,2 who received brolucizumab during the HAWK trial. Based on current information, brolucizumab is contraindicated in information would be updated, the brolucizumab 6 mg, or aflibercept 2 mg. the presence of active inflammation.2 company said. In HARRIER, eyes were randomized In addition, if inflammation is noted 1:1 to brolucizumab 6 mg or aflibercept following injection, close follow-up and Why It Was Approved 2 mg. imaging are warranted, as some cases The drug’s performance in clinical trials Visual outcomes. The researchers of occlusive vasculitis may initially be suggested that it might help retina spe- found that improvements in best-cor- subtle and others may have a delayed cialists address two continuing issues of rected visual acuity (BCVA) obtained presentation.2 anti-VEGF therapy—persistent retinal with the 6-mg dose of brolucizumab In response to these concerns, fluid despite treatment and the burden were noninferior to acuity gains with Novartis, the drug’s manufacturer, on patients of monthly anti-VEGF 2 mg of aflibercept, at both 48 and 96 launched an extensive safety review. injections. weeks.4 Approximately a third of eyes In early April, the company concluded Overview of trials. Two random- in both studies gained at least 15 letters that “there is a confirmed safety signal ized controlled multinational trials of of BCVA at 48 weeks. These gains were of rare adverse events of ‘retinal vascu- brolucizumab—known as HAWK and maintained in the second year, with a litis and/or retinal vascular occlusion HARRIER—were conducted in 1,817 mean increase in BCVA of 5.9 letters with or without presence of intraocular patients with neovascular AMD. In for brolucizumab 6 mg versus 5.3 inflammation that may result in severe HAWK, patients’ eyes were randomized letters for aflibercept in HAWK, and vision loss.’”3 As a result, prescribing 1:1:1 to receive brolucizumab 3 mg, 6.1 letters versus 6.6 letters, respectively, in HARRIER. Sustained drying of fluid. Along BY LINDA ROACH, CONTRIBUTING WRITER, INTERVIEWING PRAVIN U. with achieving their primary endpoint DUGEL, MD, K. BAILEY FREUND, MD, ANDREAS K. LAUER, MD, AND of noninferiority in BCVA, the trials

NICOLAS A. YANNUZZI, MD. demonstrated that the 6-mg dose of Novartis

30 • JUNE 2020 brolucizumab was better than afliber- frequent injections. The brolucizumab said Andreas K. Lauer, MD, at the Casey cept at drying fluid in the retina and trials showed that, if the drug proved Eye Institute in Portland, Oregon. Most at reducing central subfield thickness efficacious for a patient early in the of the cases of inflammation observed (CST). trial, their disease likely would remain in the trials resolved with no sequelae;1 In HARRIER, 24% of the brolucizu- controlled with 12-week intervals, nonetheless, their occurrence prompted mab group had intra- and/or subretinal without a T&E protocol. the push to have clinicians track and fluid at 96 weeks, compared to 39% of Additional thoughts on T&E. As report their experiences with patient the aflibercept group (p < 0.0001). In approved, brolucizumab is labeled for outcomes.2 HAWK, the comparable figures were three monthly loading doses, followed What’s next? In addition to updat- 24% and 37%, respectively (p < 0.0001). by an immediate jump to intervals of ing prescribing information, Novartis In addition, fewer eyes receiving bro eight to 12 weeks. This does not allow has informed investigators who are lucizumab 6 mg had fluid beneath for the more cautious, gradual T&E participating in ongoing clinical trials the retinal pigment epithelium at 96 protocols that many retina specialists and is amending protocols to include weeks: 17% versus 22% for aflibercept have adopted with other anti-VEGF the new safety information.3 in HARRIER, and 11% versus 15%, drugs, said K. Bailey Freund, MD, with Clinicians are encouraged to report respectively, in HAWK. Vitreous Retina Macula Consultants of any problems to Novartis at www. CST reduction. In HARRIER, opti- New York in New York City. report.novartis.com or to the FDA at cal coherence tomography (OCT) scans “I would be hesitant to use broluci- www.accessdata.fda.gov/scripts/med showed that the mean absolute decrease zumab for eyes in which I think it will watch/index.cfm. Retina specialists may in CST from baseline at 96 weeks was not be possible to extend to eight-week also contact www.asrs.org/clinical/ –198 µm in the brolucizumab subjects intervals,” Dr. Freund said. “Also, I adverse-events-reporting/report-an- and –155 µm in aflibercept eyes (p < prefer to extend gradually; so, after adverse-event. 0.0001). In HAWK, the reductions were two monthly doses, I might next try What role does COVID-19 play? –175 µm for brolucizumab and –149 a six- or seven-week interval before With the advent of COVID-19, retina µm for aflibercept (p = 0.0057). attempting to extend further.” specialists are focusing on their most Less frequent dosing. Given the vulnerable patients, including those at treatment burden posed by frequent Adverse Outcomes greatest risk of vision loss from AMD. anti-VEGF injections, many clinicians Trial results. Brolucizumab was gener- As Dr. Freund put it, “Neovascular have hoped that brolucizumab would ally well tolerated in HAWK and HAR- AMD doesn’t care about the virus, and provide patients with some relief on RIER. However, the results raised some patients can lose vision if they do not this front. concerns regarding inflammation, as a continue treatment.” Investigators in HAWK and HAR- small number of patients who received Even before COVID-19 became a RIER tested the efficacy of transition- brolucizumab experienced uveitis, concern, Dr. Freund said that his large ing patients to a quarterly injection iritis, and endophthalmitis.2 group practice was moving cautiously schedule immediately after three initial “In the phase 3 trials, there was a on adoption of the drug. Initially, he monthly loading doses, without the greater proportion of study patients planned to use brolucizumab in two gradual treat-and-extend (T&E) pro who developed intraocular inflamma- groups of patients: 1) those in whom cess that is being used off-label to tion—more so than we saw with ran- he was “unable to adequately control lengthen treatment intervals with ibizumab, aflibercept, or bevacizumab,” exudation with the other anti-VEGFs” other anti-VEGF agents. At one year, half of the brolucizumab patients were successfully on a quarterly injection schedule. Of those patients, Method of Action 82% in HAWK and 75% in HARRIER Brolucizumab is a recombinant, humanized single-chain antibody fragment— were maintained on 12-week intervals the smallest functional portion of an antibody molecule—that inhibits all for the second year.4 (Brolucizumab isoforms of VEGF-A. It has a molecular weight of 26 kDa, compared to 97-115 recipients who failed the quarterly kDa for aflibercept (Eylea) and 48 kDa for ranibizumab (Lucentis).1 regimen were treated every eight weeks Because of its small size, the molecule can be delivered into the vitreous for the remainder of the trials, without at molar doses much higher than previous anti-VEGF drugs, allowing greater the possibility of extension to every 12 penetration into retinal tissue and possibly explaining its extended duration in weeks; aflibercept was given at eight- the eye. For instance, the equivalent molecules per injection is 0.5 for ranibi- week intervals in both studies.) zumab 0.5 mg, 1 for aflibercept 2.0 mg, and 11 for brolucizumab 6.0 mg.1 Predicting response to therapy. Evidence from animal studies also suggests that its smaller size may foster One of the conundrums of anti-VEGF quicker systemic clearance.2 therapy has been in trying to predict which retinas require monthly ther- 1 Nguyen QD et al. Ophthalmology. Published online Jan. 17, 2020. apy and which will do well with less 2 Yannuzzi NA, Freund KB. Clin Ophthalmol. 2019;13:1323-1329.

EYENET MAGAZINE • 31 and 2) those “currently on a T&E enters routine clinical practice, said Dr. Coming in the next regimen where I would like to extend Yannuzzi. the injection interval a bit further,” Good results with PCV. Dr. Freund ® Dr. Freund said. Now, however, he has noted that a potential target population suspended his use of brolucizumab for use of the drug as initial monother- while he awaits additional findings on apy would be patients who have polyp- the drug’s safety. oidal choroidal vasculopathy (PCV), a Feature subtype of neovascular AMD in which Cataract Astigmatism Further Clarification Needed typical soft drusen are often absent but management: How to take Presuming that brolucizumab regains eyes have pachychoroid disease features. a stepwise approach. its footing, a number of issues warrant This AMD variant is most common in EyeWiki The Academy’s additional investigation. Asian populations. Incidence of this clinical wiki celebrates its Stable disease? Some evidence subtype among Asians with neovas- 10th anniversary. A look at suggests that brolucizumab might cular AMD has been estimated to be 6 this popular reference over smooth out fluctuations in retinal as high as 50%, and there is early the past decade. thickness over time, said Pravin U. evidence that brolucizumab might Dugel, MD, with Iveric bio, Inc. and dry up their lesions quickly, he said. Clinical Update based in Phoenix. In post hoc analyses of the brolucizumab data, OCTs taken 1 aao.org/headline/brolucizumab-s-safety- Glaucoma Three experts discuss traditional filtering of brolucizumab eyes did not have the under-review. Accessed March 12, 2020. surgeries in the first in- seesaw pattern observed in those taken 2 Nguyen QD et al. Ophthalmology. 2020. Pub- stallment of this two-part of aflibercept eyes, he said—and in lished online Jan. 17, 2020. roundtable. other trials of anti-VEGF agents, fewer 3 www.novartis.com/news/novartis-completes- OCT fluctuations correlated with better safety-review-and-initiates-update-beovu-pre Retina What retina surgeons BCVA, he noted. scribing-information-worldwide. Accessed April need to know about operat- If fewer OCT fluctuations are indeed 13, 2020. ing on COVID+ patients. substantiated with brolucizumab, this 4 Dugel PU et al. Ophthalmology. 2020;127(1):72- would be one of the most appealing 84. Pearls aspects of the drug for clinicians, Dr. 5 Campochiaro PA et al. Ophthalmology. 2019;12 Retinitis Pigmentosa, Lauer said. “We know that a consistently 6(8):1141-1159. Review research on Part 2 sustained level of medication reduces 6 Takahashi A et al. Ophthalmol Retina. 2018;2(4): current management, and reactivation of the disease, and the clin- 295-305. get up to speed on promis- ical picture tends to be more stable,” he ing new therapies. said. Support for this comes “from the Dr. Dugel served as principal investigator of inflammatory eye disease world, using HAWK and is executive vice president and chief Savvy Coder sustained release corticosteroids, and strategy and business officer of Iveric bio. He is Make 5 New Rules for E/M also from the LADDER study, with a based in Phoenix. Relevant financial disclosures: sure your practice is ready port delivery system using ranibizu Iveric bio: E; Novartis/Alcon Pharmaceuticals: C; for new coding rules. mab,” Dr. Lauer said. Roche/Genentech: C. Impact as drying agent. “The data Dr. Freund practices at Vitreous Retina Macular Blink suggest that at the fixed interval dosing Consultants of New York and is clinical professor Take a guess at the next regimens evaluated in the clinical trial, of ophthalmology at the New York University issue’s mystery image. brolucizumab appears to be a better School of Medicine, both in New York City. Rele- drying agent than aflibercept,” said vant financial disclosures: Novartis/Alcon Pharma- Nicolas A. Yannuzzi, MD, at Bascom ceuticals: C; Optovue: C; Roche/Genentech: S. For Your Convenience Palmer Eye Institute in Miami. “But Dr. Lauer is chair of ophthalmology and chief of These stories also will be how much does that matter? Visual the Retina-Vitreous Division of the Casey Eye In- available online at outcomes were shown to be noninfe- stitute at Oregon Health & Science University in aao.org/eyenet. rior.” Portland. Relevant financial disclosures: Allergan: S; In addition, Dr. Yannuzzi noted, Biogen: C; Genentech: S; NEI: S; Nightstar/Biogen: FOR ADVERTISING INFORMATION some retina specialists are wary of the C; Oxford BioMedica: S; Regenxbio: C; Sanofi: C. idea of completely drying the neo- Dr. Yannuzzi is a fellow in retina and vitreous Mark Mrvica or Kelly Miller vascularization for fear of hastening diseases, an instructor, and chief ophthalmology M. J. Mrvica Associates Inc. progression to geographic atrophy. resident at Bascom Palmer Eye Institute in Miami. 856-768-9360 At any rate, evidence of any benefit Relevant financial disclosures: None. [email protected] of extended dosing and lower treatment See the disclosure key, page 9. For full disclosures, burden will have to wait until the drug view this article at aao.org/eyenet.

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