A new formulation of bevacizumab for neovascular age-related macular degeneration (nAMD) is headed for evaluation by the US Food and Drug Administration (FDA) amid controversy about a phase 3 trial.
FDA approval would set bevacizumab-vikg (Lytenava) apart from formulations from compounding pharmacies currently sold for off-label ophthalmic use, said Firas M. Rahhal, MD, an associate clinical professor of ophthalmology at the University of California, Los Angeles.
"There are different standards of purification," Rahhal told Medscape Medical News. "Those standards are quite high when you have an ophthalmic product."
He presented the findings of the NORSE 2 clinical trial here at the American Academy of Ophthalmology (AAO) 2021 annual meeting. Outlook Therapeutics plan to apply for FDA approval in the first quarter of 2022, Rahhal said.
But NORSE 2, while characterized as a "superiority" trial, used a more intensive dosing schedule for bevacizumab-vikg than for ranibizumab. The comparison is "apples to oranges," said Anat Loewenstein, MD, MHA, chair of the Department of Ophthalmology at Tel Aviv Sourasky Medical Centre and professor of ophthalmology at Tel Aviv University in Israel.
"Everyone is thrilled with the idea that there may be a drug that's bevacizumab, designed for ophthalmic use, and we will be able to use it," she told Medscape Medical News. "So everyone was really waiting for this study, but the problem is that the design is very, very strange."
Genentech obtained FDA approval for bevacizumab (Avastin) to treat cancer and ranibizumab (Lucentis) to treat nAMD. It never sought FDA approval for bevacizumab as an ophthalmic drug, but because the two are molecularly similar and bevacizumab is less expensive, clinicians began using bevacizumab off-label for nAMD and other retinal conditions.
The difference in cost is stark, Rahhal said. Purchased from a compounding pharmacy, bevacizumab costs about $55 per injection, while ranibizumab costs about $1,800 per injection. And the 2011 Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) showed that bevacizumab could match ranibizumab in improving patients' visual acuity.
That has made bevacizumab the most widely used drug for nAMD, accounting for about half the US market, with ranibizumab and a newer drug, aflibercept (Eylea), dividing the rest. In some countries, bevacizumab is virtually the only drug used for this indication, while others have not allowed it because of the lack of approval for this indication, Rahhal said.
But the compounded bevacizumab comes with drawbacks. There have been outbreaks of endophthalmitis traced to impurities. Doses are sometimes irregular. And bubbles of silicon oil from syringes have been injected into some patients' eyes. While these issues have improved in recent years, they remain troublesome, Rahhal said.
So when bevacizumab approached the end of its patent, Outlook Therapeutics saw an opportunity. The drug company formulated bevacizumab for ophthalmic use and designed three clinical trials, NORSE 1, 2, and 3. NORSE 1 and 3 — whose results were announced first — focused on safety, while NORSE 2 provided the evidence of efficacy.
While many new drugs are pitted against established treatments in "noninferiority" trials such as CATT, the Outlook leadership instead chose a superiority trial. For statistical reasons, fewer patients are needed in superiority trials, cutting the cost of the trial and expediting its completion, Rahhal said.
The trial enrolled 228 patients with nAMD at 39 clinical trial sites in the United States; 99% of the patients were White and 60% were women, with a median age of 79. Demographics, baseline best-corrected visual acuity (BCVA), and central foveal thickness were similar between the two study groups.
In one group, 113 patients received 12 bevacizumab-vikg injections: one each month for 12 months.
In the other group, 115 patients received five ranibizumab injections: one each at months 1, 2, 3, 6, and 9. In months 4, 5, 7, 8, 10, and 11, they received sham injections and, in month 12, they received no injection.
To no one's surprise, patients in the bevacizumab-vikg group fared better, with 41.7% gaining at least 15 ETDRS letters, compared with 23.1% in the ranibizumab group, and the difference was significant (P = .0052).
Adverse events were similar in the two groups, with 45.1% of patients experiencing treatment-emergent ocular adverse events in the bevacizumab-vikg group versus 41.7% in the ranibizumab group. There was one serious ocular adverse event (increased intraocular pressure requiring paracentesis) in the bevacizumab-vikg group and none in the ranibizumab group.
The presentation drew immediate criticism at the meeting from some panel discussants. While he's looking forward to an FDA-approved version of bevacizumab, the study is "disingenuous," said Colin McCannel, MD, a professor of clinical ophthalmology at the University of California, Los Angeles. "I think Lytenava may face a litany of adoption problems because of the study design."
The criticism is "a reasonable point," Rahhal said. The trial doesn't prove that bevacizumab-vikg is superior to ranibizumab, he acknowledged. Rather than a head-to-head comparison of the two drugs, the study was designed to meet the FDA's standard of evidence that bevacizumab-vikg works well. "It achieves the regulatory accomplishments and milestones in a much quicker and expeditious way."
The ranibizumab dosing in NORSE 2 is based on the 2008 PIER study, in which ranibizumab was administered monthly for 3 months, then quarterly. That protocol is in the drug's FDA label, which made it fair game for a comparison, he said.
Loewenstein predicts that the study design will give clinicians pause, but if bevacizumab-vikg is reasonably priced, many will adopt it anyway. "If the price is reasonable, we will use it," she said.
Loewenstein has reported relationships with Allergan, Bayer Healthcare, Beyeonics, ForSight Labs, Notal Vision, Novartis, and Roche. Rahhal has reported relationships with Alcon, Almira Sciences, Alpine Bio Therapeutics, Beaver-Visitec International, Re-Vana Therapeutics, ZEISS, Envision Diagnostics, and ExSight Ventures, as well as Outlook Therapeutics. The study was funded by Outlook.
AAO 2021 Annual Meeting. Presented November 13, 2021.
Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH
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