Blog | 3/26/2025

nAMD: Gene Therapies vs. TKIs… Who Will Win?

By Patrick Symmonds and Isileli Kakala

Introduction

Neovascular age-related macular degeneration (nAMD) is a severe form of retina degeneration characterized by abnormal angiogenesis that damages the macula. nAMD is the leading cause of blindness in the US in older adults, and sales in the US market size for nAMD treatments exceeded $5B USD in 2024. Novel nAMD treatments have the potential for high patient impact while being compelling business opportunities for drug developers. The current standard of care relies on anti-VEGF therapies, which are generally effective. However, anti-VEGFs require frequent intravitreal injections and researchers have found that 15-50% of patients respond suboptimally.1-6 Emerging treatment modalities including tyrosine kinase inhibitors (TKIs) and gene therapies aim to improve durability, reduce treatment burden, and provide long-term disease control, representing a potential shift in the treatment landscape.

Current Standard of Care: Anti-VEGF Therapies

Anti-VEGF therapies have long been the cornerstone of treatment for nAMD. By inhibiting VEGF, these treatments help reduce choroidal neovascularization, vascular leakage, and subsequent retinal damage. Currently, five anti-VEGF therapies are used: aflibercept (Eylea, Eylea HD), ranibizumab (Lucentis and other biosimilars), brolucizumab (Beovu), compounded bevacizumab, and faricimab (Vabysmo). Faricimab, a bispecific antibody, also targets ANG2, providing an alternative mechanism to address nAMD.

Figure 1

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However, despite their effectiveness, anti-VEGF therapies come with certain challenges. One of the main drawbacks is the need for intravitreal injections every 1-4 months, which are burdensome for patients. Regular injections are necessary to maintain the therapeutic effect and prevent disease progression, leading to a significant treatment burden. Additionally, some patients showcase suboptimal responses to anti-VEGF due to a reduction or lack of meaningful improvements to visual acuity, persistence of inflammation, and unresolved or new retinal damage (i.e. scarring, hemorrhages, fibrosis).

Emerging Technologies to Treat nAMD: TKIs and Gene Therapies

Two promising emerging therapies are tyrosine kinase inhibitors (TKIs) and gene therapies (GTx). Both aim to reduce the frequency of treatments and improve patient outcomes. Both technologies have advanced to Phase III clinical trials by multiple developers.

Figure 2

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TKIs target multiple pathways in the disease process, including VEGF, PDGF, and Tie2 receptors. These inhibitors work intracellularly to prevent tyrosine kinase phosphorylation, reducing choroidal neovascularization and fluid accumulation. Through more robust and comprehensive target coverage, TKIs may offer a novel mechanism of angiogenesis suppression.

TKIs are formulated with extended-release technologies, enabling long-term and controlled drug delivery, reducing the frequency of treatments to bi-annual injections. This significantly lowers the treatment burden for patients compared to the 1- to 4-month intervals of current anti-VEGF therapies.

The longer treatment intervals and broader target coverage may make TKIs particularly beneficial for patients who do not respond optimally to current anti-VEGF therapies.

GTx utilize adeno-associated virus (AAV) viral vectors to introduce a plasmid that encodes for anti-VEGF proteins into retinal cells. The GTx essentially leverages cellular machinery to produce therapeutic proteins that inhibit VEGF on an ongoing basis.

GTx offer the potential for a one-time treatment providing permanent suppression of VEGF, significantly reducing the treatment burden for patients. For this reason, GTx may be best suited for patients who respond well to anti-VEGF therapies and prefer a long-duration option.

Figure 3

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Comparing Efficacy, Safety, and Treatment Frequency

When comparing TKIs and GTx, several factors come into play:

  • Efficacy: Given the broader target coverage, TKIs may show better efficacy in patients who fail to respond optimally to anti-VEGF therapies. Comparatively, GTx are expected to offer equal efficacy with much fewer treatments for those who have responded well to current anti-VEGF treatments.
  • Treatment Frequency: TKIs require bi-annual treatments whereas GTx are targeting the convenience of a single-dose treatment.  Both are likely to be preferred options by patients as they are substantially better than the current treatment burden of 1-4 months.

From the clinician’s perspective, retina specialists may prefer the opportunity to provide ongoing treatment with TKIs along with nAMD monitoring and screening for other ophthalmology conditions. Alternatively, GTx are likely to offer a high, but one-time, reimbursement to retina specialist practices.   

  • Safety: TKIs have reported mild to moderate adverse events and risks of these events are likely to persist with ongoing treatment. GTx have reported moderate to severe events, including ocular inflammation requiring treatment, but patients are exposed to these risks once. Long-term safety risks with GTx are unknown.

Figure 4

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Future Treatment Paradigm

The future treatment paradigm for nAMD will likely have two exciting and compelling new options for patients and clinicians: TKIs and GTx. TKIs are poised to become the best alternative for patients who do not respond well to anti-VEGF therapies due to their favorable profile in eligible patients, efficacy, and safety. GTx will be the best long-duration anti-VEGF option for those who respond well to anti-VEGF therapies but look to greatly reduce their treatment burden.

Figure 5

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So, Who Will Win? 

Both TKIs and GTx hold promise for revolutionizing the treatment of nAMD. The choice between these therapies will depend on individual patient responses and preferences, but together, they represent a significant advancement in the fight against this debilitating disease. To answer the question of who will win in this future state of TKIs and GTx: the answer is patients, who will have more options to help them successfully manage nAMD.

 

Sources

1 Tsai 2023 BMC Ophthalmol.

2 Mettu 2021 Prog Retin Eye Res.

3 Bobadilla 2022 Biomedicines

4 Suzuki 2014 Br J Ophthalmol.

5 Krebs 2013 Br J Ophthalmol.

6 Lux 2007 Br J Ophthalmol.

Authors

  • Patrick Symmonds is a Senior Director in our biopharma practice, where he focuses on building the firm's expertise in ophthalmology and other therapeutic areas.
  • Isileli Kakala is an analyst in our biopharma and digital health & enterprise HIT practices. 

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