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Reinventing Treatment: Bevacizumab-vikg in the Battle Against Wet Age-related Macular Degeneration

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Published Online: Dec 7th 2023 touchREVIEWS in Ophthalmology. 2023;17(2):2-3 DOI: https://doi.org/10.17925/USOR.2023.17.2.3
Authors: Dhanashree Ratra, Aashna Ratra
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Abstract
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Article Information
Abstract:
Overview

Bevacizumab-vikg, an investigational ophthalmic formulation of bevacizumab, is on the threshold of being approved for on-label use in wet age-related macular degeneration. A phase III clinical trial found that this drug showed superior efficacy and comparable safety to ranibizumab. If approved by the US Food and Drug Administration and priced right, it will likely replace the current off-label compounded bevacizumab. In that case, bevacizumab-vikg would help eliminate the risks of contamination, reduced potency and availability often associated with the use of compounded medicines. It will be interesting to witness the impact this drug will have on how clinicians treat wet age-related macular degeneration.

Keywords

Anti-vascular endothelial growth factorbevacizumabcompounding pharmaciesoff-label drugsranibizumabwet age-related macular degeneration

Article:

Age-related macular degeneration (AMD) is a progressive eye condition that affects millions of people worldwide and poses a significant threat to vision in individuals over the age of 50.1 Of the two types of AMD, wet AMD, which is characterized by the growth of a choroidal neovascular membrane, is responsible for approximately 90% of the vision loss observed in patients with AMD.1 Traditionally, treatments for wet AMD have primarily centred around the inhibition of vascular endothelial growth factor (VEGF), which is responsible for promoting neovascularization. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has already demonstrated its efficacy in treating various forms of cancer by hindering angiogenesis.2 It also has been used for treating wet AMD for over a decade, albeit as an off-label treatment.3 Bevacizumab-vikg, an innovation of bevacizumab formulated specifically for ophthalmic use, signals a new chapter in the fight against wet AMD.

Bevacizumab-vikg (ONS-5010/LYTENAVA™; Outlook Therapeutics, Inc., Cranbury, NJ, USA) has undergone clinical trials to demonstrate its safety and efficacy in wet-AMD treatment. Outlook Therapeutics has filed a Biologics License Application with the US Food and Drug Administration, and if approved, it will be the first and only approved bevacizumab for ophthalmic indications. Of the clinical trials conducted, NORSE ONE was a proof-of-concept clinical experience trial (N=61) conducted at nine trial sites in Australia. It compared bevacizumab-vikg to ranibizumab (LUCENTIS®Genentech, South San Francisco, CA, USA) in the treatment of wet AMD and showed the first evidence of the efficacy and safety of this treatment in humans.4 NORSE TWO, the pivotal phase III registration clinical trial, enrolled a total of 228 patients with wet AMD at 39 clinical trial sites in the United States.5 It was designed as a superiority trial. The bevacizumab-vikg was administered monthly against ranibizumab, which was administered according to the PIER (Phase IIIb, multicenter, randomized, double-masked, sham Injection–controlled study of the Efficacy and safety of Ranibizumab) dosing regimen6 described in the ranibizumab label, that is, three monthly doses followed by quarterly doses. In this trial, both the primary and secondary endpoints were achieved with high statistical significance and clinical relevance. The primary endpoint, a gain of ≥15 letters of vision, was seen in 41.7% of patients in the bevacizumab-vikg group versus 23.0% of those in the ranibizumab group (p=0.0052). Further, 56.5% of patients in the bevacizumab-vikg group gained ≥10 letters of vision (p=0.0016), and 68.5% gained ≥5 letters of vision (p=0.0116). The key secondary endpoint was a mean change in best-corrected visual acuity from baseline to month 11. In the bevacizumab-vikg arm, there was a gain of 11.2 letters compared with 5.8 letters in the ranibizumab arm (p=0.0043).5 NORSE THREE was an open-label safety study required for the Biologics License Application submission of bevacizumab-vikg (N=197). Overall, the drug was well tolerated and showed a strong safety profile, with only one adverse event of ocular inflammation reported across all three trials.7

However, the design of the NORSE TWO trial received some criticism on account of the infrequent dosing of the comparator ranibizumab. In the CATT trial (ClinicalTrials.gov identifier: NCT00593450), a monthly administration of bevacizumab was shown to be equivalent to a monthly administration of ranibizumab.8 Quarterly dosing of ranibizumab is shown to be inferior to monthly dosing of ranibizumab. Consequently, experts felt that comparing 12 monthly doses of bevacizumab-vikg to 5 monthly doses of ranibizumab was not fair. The company defended their stand by saying that the dosing followed was the one recommended on the label for ranibizumab. However, a large amount of data had already established the efficacy of bevacizumab.9

What makes bevacizumab-vikg attractive is that it will be dispensed as a single vial, which will completely eliminate the problems associated with fractionation and repackaging. In the past, several episodes of endophthalmitis were traced back to the compounding pharmacies.10,11 Furthermore, bevacizumab has problems with inconsistent dosing and bioavailability. Small droplets of silicone oil have also been reported inside the vitreous, and these have been observed to arise from the syringes used to prepare the aliquots of bevacizumab.10 Moreover, several practitioners are uncomfortable with using an off-label product, as it can cause many issues, ranging from legal and ethical issues to lack of reimbursement and increased risk of adverse events. Thus, bevacizumab-vikg has the potential to enhance the therapeutic outcomes and convenience of treatment.

The main advantage of the off-label bevacizumab lies in the reduced treatment cost. The cost of compounded bevacizumab is between US$25 and US$50.12 It might not be practical for Outlook Therapeutics to set such a low price. The speculated price for bevacizumab-vikg ranges anywhere from US$100$ to US$1,000 or more.13 With the market becoming overcrowded with several new biosimilars and innovator molecules, the competition is fierce. However, if priced reasonably lower than the approved molecules and their biosimilars, bevacizumab-vikg would be a welcome new drug, especially in countries where off-label drugs are not permitted.12,13

However, experts are concerned that the availability of on-label bevacizumab-vikg is likely to paradoxically increase the costs to the healthcare systems and patients.14 With the approval of bevacizumab-vikg by the US Food and Drug Administration, the compounding of the off-label bevacizumab will have to be stopped under the Drug Quality and Security Act, which stipulates that voluntary facilities cannot compound a copy of approved drugs. Compounded bevacizumab will be considered a copy of the approved on-label bevacizumab-vikg. Significant speculation exists around this law, but regardless of the regulations, the availability of compounded bevacizumab might be affected. After calculating the average sales prices of anti-VEGFs in the United States, it was determined that the best way to continue to offer affordable medical care to patients would be to grant an exemption to this law on the use of repackaged intraocular bevacizumab.14

In conclusion, bevacizumab-vikg is a promising new formulation for on-label ophthalmic use to treat wet AMD. If approved, it would offer a more convenient treatment option, as a single dose vial would eliminate the problems inherent to fractionation and compounding. If priced right, it has the potential to impact the way we treat wet AMD.

Article Information:
Disclosure

Dhanashree Ratra and Aashna Ratra have no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This article is an opinion piece and does not report on new clinical data, or any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review.

Authorship

The named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Correspondence

Dhanashree RatraDepartment of Vitreoretinal DiseasesSankara Nethralaya, Medical Research Foundation41/18, College Road, Chennai – 600 006Tamil NaduIndiadhanashreeratra@gmail.com

Support

No funding was received in the publication of this article.

Access

This article is freely accessible at touchOPHTHALMOLOGY.com. © Touch Medical Media 2023.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the writing of this article.

Received

2023-08-21

References

1. Bressler NMBressler SBFine SLAge-related macular degenerationSurv Ophthalmol1988;32:375413. DOI10.1016/0039-6257(88)90052-5.

2. Steinbrook RThe price of sight—Ranibizumab, bevacizumab, and the treatment of macular degenerationN Engl J Med2006;355:140912DOI10.1056/NEJMp068185.

3. Kim LAD’Amore PAA brief history of anti-VEGF for the treatment of ocularAm J Pathol2012;181:3769. DOI10.1016/j.ajpath.2012.06.006.

4. Outlook TherapeuticsOutlook Therapeutics Completes Patient Enrollment for NORSE 1 a Phase 3 Clinical Trial for ONS-5010 in Wet AMD2019Available at: https://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-completes-patient-enrollment-norse-1-phase (Date last accessed: 30 November 2023).

5. Outlook TherapeuticsOutlook Therapeutics presents NORSE TWO phase 3 pivotal safety and efficacy data for ONS-5010/LYTENAVA™ (bevacizumab-vikg) at the Retina Subspecialty Day, American Academy of Ophthalmology (AAO) 2021 Annual Conference2021Available athttps://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-presents-norse-two-phase-3-pivotal-safety (Date last accessed23 November 2023).

6. Regillo CDBrown DMAbraham Pet alRandomized, double-masked, sham-controlled trial of Ranibizumab for Neovascular age-related macular degeneration: PIER study year 1Am J Ophthalmol2008;145:23948. DOI10.1016/j.ajo.2007.10.004.

7. Outlook TherapeuticsOutlook Therapeutics’ Positive NORSE THREE Safety Data Presented at 2021 American Society of Retina Specialists for ONS-5010 Ophthalmic Bevacizumab2021Available athttps://ir.outlooktherapeutics.com/news-releases/news-release-details/outlook-therapeutics-positive-norse-three-safety-data-presented (Date last accessed30 November 2023).

8. CATT Research GroupMartin DFMaguire MGet alRanibizumab and bevacizumab for neovascular age-related macular degenerationN Engl J Med2011;364:1897908DOI10.1056/NEJMoa1102673.

9. MedscapeBevacizumab-vikg Wet AMD Trial Raises Eyebrows2021Available atwww.medscape.com/viewarticle/962906?form=fpf (Date last accessed1 December 2023).

10. Schmucker CEhlken CAgostini HTet alA safety review and meta-analyses of bevacizumab and ranibizumab: Off-label versus gold standardPLoS One2012;7:e42701DOI10.1371/journal.pone.0042701.

11. VanderBeek BLBonaffini SGMa LAssociation of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol2015;133:115964DOI10.1001/jamaophthalmol.2015.2556.

12. Sharma AKumar NParachuri Net alOn label bevacizumab for retina: Where it standsEye (Lond)2022;36:9167DOI10.1038/s41433-021-01909-z.

13. Clinical trials arenaOutlook Therapeutics’ bevacizumab-vikg for wet AMD has experts anticipating Phase III success, but biased design likely to limit uptake2021Available atwww.clinicaltrialsarena.com/comment/outlook-therapeutics-bevacizumab-vikg-for-wet-amd-has-experts-anticipating-phase-iii-success-but-biased-design-likely-to-limit-uptake/?cf-view (Date last accessed1 December 2023).

14. Zhang CFriedman SMruthyunjaya PParikh R. The biosimilar paradox: How anti-vascular endothelial growth factor biosimilars could increase patient and overall health care costsOphthalmology 202323002956. doi:10.1016/j.ophtha.2023.04.019

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