Intravitreal Bevacizumab Receives EU Approval for Wet AMD Treatment

On 28 May 28 2024, the European Commission (EC) granted marketing authorization for ONS-5010 (Lytenava^™), an intravitreal bevacizumab from Outlook Therapeutics (New Jersey, USA), for treating wet age-related macular degeneration (wet AMD).

“This is a landmark milestone for us,” said Outlook Therapeutics’ President and CEO Russell Trenary in a news release. “We are extremely pleased to receive Marketing Authorization for Lytenava in the EU and are moving toward our potential first commercial launch in an EU Member State in the first calendar quarter of 2025.¹

This approval marks a potentially significant shift from the previous reliance on off-label IV bevacizumab (Avastin^®, Roche/Genentech) sourced from compounding pharmacies which posed contamination risks and potency variations, among a host of other issues.^2,3

“Ophthalmologists need to have a bevacizumab formulation that is produced with good manufacturing compliance. Lack of sterility, presence of particles, endotoxin, and concentration are uncontrolled with preparation by compounding pharmacies.” asserted Prof. Dr. med. Gerd U. Auffarth, medical director of Heidelberg University Eye Clinic and member of Outlook Therapeutics’ board of directors. 

“There’s a need for patient safety. But also, the efficacy is better if you have the right formulation that stays in the eye, that stays within the vitreous cavity, and that doesn’t interact negatively with the other tissues there, which could result in systemic side effects,” he added.

While similar on-label drugs exist, they are costly. Approval of ONS-5010 may offer a more affordable option and eliminate the need for off-label intravitreal bevacizumab use. This long-awaited green light marks the culmination of a rigorous journey, propelled by mounting evidence of bevacizumab’s efficacy in combating retinal ailments. 

The evidence

Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (anti-VEGF), inhibits abnormal blood vessel development and reduces vascular leakage. 

Like other anti-VEGFs, bevacizumab was originally developed as a treatment for various cancers. Its effectiveness in curbing abnormal blood vessels caught the attention of ophthalmologists seeking new strategies for treating retinal diseases.

Dr. Philip Rosenfeld pioneered the research on intravitreal bevacizumab. In his 2005 study, patients with wet AMD who did not respond well to pegaptanib therapy received an intravitreal injection of bevacizumab. Within one week, optical coherence tomography showed resolution of the subretinal fluid, resulting in a normal-appearing macular contour. The improved macular appearance was maintained for at least four weeks, with visual acuity remaining stable, and no inflammation observed. These positive results led to the widespread off-label use of intravitreal bevacizumab globally.⁴ 

“I think in Western Europe, we administer around eight to nine million, up to ten million [intravitreal anti-VEGF] injections. And of those, at least 30% to almost 50%, depending on the country, are off-label Avastin use,” claimed Prof. Auffarth.

Studies like the Comparison of wet AMD Treatment Trials (CATT) and the Inhibition of VEGF in Age-related Choroidal Neovascularization (IVAN) trial further supported the use of bevacizumab for wet AMD, demonstrating similar efficacy to other anti-VEGFs like ranibizumab.^5,6

The cost-benefit

With other approved ophthalmic formulations of anti-VEGFs on the market—ranibizumab (Lucentis^®; Genentech/Roche), pegaptanib (Macugen^®; Eyetech Pharmaceuticals/Pfizer), and aflibercept (EYLEA^®; Bayer/Regeneron)—why the push for on-label intravitreal bevacizumab? 

A 2023 report by the Institute for Accountable Care revealed that Avastin was significantly less expensive than Eylea and Lucentis for treating wet AMD. Avastin costs between $50 to $100 per dose, while Eylea and Lucentis cost around $1,800 to $2,000 per treatment. Given that these medications require multiple doses over the course of treatment, the total amount can add up significantly.⁷

Off-label bevacizumab’s affordability and efficacy in ophthalmology have led to its widespread adoption in clinical practice, earning it a place on the World Health Organization’s essential medicines list. Notably, none of the previously approved intravitreal anti-VEGFs make the cut.⁸

The introduction of ONS-5010 could significantly impact market dynamics. If priced lower, Lytenava will be an attractive option for clinicians and patients seeking effective and affordable treatment for wet AMD. 

However, the ophthalmic anti-VEGF arena is becoming increasingly competitive with the recent FDA approval of two aflibercept biosimilars, Yesafili^™ (Biocon Biologics, Bengaluru, India) and Opuviz^™(Samsung Bioepis, Incheon, South Korea; and Biogen, Massachusetts, USA), as interchangeable with Eylea. These biosimilars may offer competition in terms of price and regulatory acceptance.⁹ 

The on-label journey

Outlook Therapeutics stepped up to address the demand for on-label intravitreal bevacizumab. By late 2022, the FDA accepted the company’s Biologics License Application (BLA), while the European Medicines Agency (EMA) validated its Marketing Authorization Application (MAA), both for ONS-5010 as a treatment for wet AMD.^10,11 

However, ONS-5010’s on-label journey hit a snag when the FDA sent a Complete Response Letter (CRL) in August 2023. Despite promising results from Outlook Therapeutics’ NORSE ONE and NORSE TWO Phase 3 clinical trials, along with the NORSE THREE open-label safety study, the FDA raised concerns about chemistry, manufacturing, and controls (CMC) issues. Additionally, they highlighted observations from pre-approval manufacturing inspections and requested further evidence.¹²

“Safety and efficacy are important, as well as high standards for manufacturing. The FDA also wants to ensure that inventory and distribution details are accounted for. For example, temperature issues during shipping. All of that must be regulated.” explained Prof. Auffarth.

He expressed confidence in the company’s ability to overcome these hurdles. “A lot of companies may stop the process because they don’t have the money to do another study or to address regulatory concerns,” he said. “I’m not worried that the FDA has an issue that Outlook Therapeutics cannot address.” 

Outlook Therapeutics anticipates resubmitting its ONS-5010 BLA to the FDA by the end of 2024 following the completion of the NORSE EIGHT noninferiority study and resolution of CMC comments in the CRL.¹³

The little anti-VEGF that could

The journey to ONS-5010 approval has been arduous, marked by rigorous clinical trials and regulatory scrutiny, yet it represents a significant advancement in retinal disease management. 

As Outlook Therapeutics continues to navigate regulatory processes and address FDA concerns, the future looks bright for Lytenava. However, questions remain about its cost and market share potential. Will Lytenava be able to compete effectively against other established and recently approved treatments? Only time will tell.

References

1. Outlook Therapeutics, “Outlook Therapeutics® Received European Commission Marketing Authorization for LYTENAVA™ (bevacizumab gamma) for the Treatment of Wet AMD,” news release, May 28, 2024. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-receives-european-commission-marketing. Accessed on May 28, 2024.
2. Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn’t blind people, people blind people. Am J Ophthalmol. 2012;153(2):196-203.e1.
3. Yannuzzi NA, Klufas MA, Quach L, et al. Evaluation of compounded bevacizumab prepared for intravitreal injection. JAMA Ophthalmol. 2015;133(1):32-39.
4. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36(4):331-335.
5. CATT Research Group; Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Eng J Med. 2011;364(20):1897-1908.
6. Chakravarthy U, Harding SP, Rogers CA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularization: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013;382(9900):1258-67.
7. Institute for Accountable Care, “Trends in Medicare ACO cost and use of biologic therapies to treat age-related macular degeneration,” 2023. Available at: https://www.institute4ac.org/wp-content/uploads/2023/12/IAC_Part-B-AMD-Drugs_White-Paper_Dec-2023_FINAL.pdf. Accessed on May 15, 2024.
8. World Health Organization, “WHO Model List of Essential Medicines – 23rd list,” 2023. Available at: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02. Accessed on May 15, 2024.
9. The United States Food and Drug Administration, “FDA approves first interchangeable biosimilars to Eylea to treat macular degeneration and other eye conditions,” 2024. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-interchangeable-biosimilars-eylea-treat-macular-degeneration-and-other-eye. Accessed on May 21, 2024.
10. Outlook Therapeutics, “Outlook Therapeutics® Announces Acceptance of Biologics License Application by U.S. FDA for ONS-5010 as a Treatment for Wet AMD,” news release, October 28, 2022. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-acceptance-biologics-license. Accessed on May 15, 2024.
11. Outlook Therapeutics, “Outlook Therapeutics® Announces Validation of Marketing Authorization Application by the European Medicines Agency for ONS-5010 as a Treatment for Wet AMD,” news release, December 22, 2022. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-announces-validation-marketing. Accessed on May 15, 2024.
12. Outlook Therapeutics, “Outlook Therapeutics® Provides Regulatory Update on FDA Review of ONS-5010 / Lytenava^tm (bevacizumab-vikg) for the Treatment of Wet AMD,” news release, August 23, 2023. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-provides-regulatory-update-fda-review-ons. Accessed on May 15, 2024.
13. Outlook Therapeutics, “Outlook Therapeutics® Provides Update on Type A Meetings with FDA,” news release, November 2, 2023. Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeuticsr-provides-update-type-meetings-fda. Accessed on May 15, 2024.