Wet age-related macular degeneration (Wet AMD) is the main cause of visual dysfunction and blindness in the elderly. Currently, intravitreal injection of anti-VEGF drugs has become the first-line treatment for the disease, but current anti-VEGF drugs still have many shortcomings, such as frequent injections with multiple potential risks, insensitive reactions in some patients, and low patient compliance. Therefore, it is urgent to find new therapeutic drugs.
With the deepening of the understanding of pathological mechanisms, the emergence of multi-target small molecule drugs has opened up a new path for the treatment of this disease. Compared with the traditional approach of only inhibiting VEGF, these small molecules are expected to provide new opportunities for improving efficacy, reducing treatment burden and delaying drug resistance by intervening in multiple links such as angiogenesis, inflammation and oxidative stress.

AMD, The third leading cause of blindness worldwide

Age-related macular degeneration (AMD) is an age-related, chronically progressive blinding eye disease. Globally, the incidence of AMD increases significantly with age, and the prevalence in people over 85 years old can be as high as 46.6%. It is predicted that the number of wet AMD patients worldwide will reach 288 million by 2040, and approximately 500,000 people will be blinded by this disease every year, becoming the third leading cause of blindness.

AMD is clinically divided into dry AMD and wet AMD. Wet AMD is the main clinical type causing visual impairment. Its pathological characteristics include macular RPE (retinal pigment epithelium) damage and abnormal proliferation and choroidal neovascularization (CNV). leakage. This not only affects patients’ daily activities such as reading, writing, and driving, but also has a profound impact on the medical burden of aging societies around the world.

The pathological process of wet macular degeneration begins with the thickening of Bruch's membrane and the accumulation of hyaline membranes . These changes work together with inflammation, oxidative stress and hypoxia to destroy the retinal pigment epithelium (RPE). The typical manifestation of wet AMD is the formation of choroidal neovascularization (CNV). These abnormal blood vessels are prone to rupture or leakage, further damaging the macular area.

Anti-VEGF drugs have opened a new chapter in the treatment of wet AMD, with the birth of blockbuster new drugs such as ranibizumab, aflibercept, and bevacizumab. However, current treatment methods also have their limitations, such as the need for long-term and frequent intravitreal injections, the increased risk of adverse reactions such as intraocular inflammation after multiple injections, and the development of drug resistance in some patients, and the economic burden on patients cannot be ignored.

In recent years, research on multi-target small molecule drugs targeting angiogenesis and inflammation has brought new hope for the treatment of wet AMD and is expected to break through the limitations of traditional VEGF inhibitors.
VEGF

A revolutionary chapter in targeted therapy for wet AMD

Anti-VEGF (vascular endothelial growth factor) therapy is regarded as a milestone treatment for wet AMD and is currently the main treatment for the disease. It protects the macula by inhibiting the activity of abnormal new blood vessels in the eye, reducing exudation and bleeding.

When it comes to the topic of inhibiting angiogenesis, one can't help but think of the 2010 TED speaker Dr. William Li's lecture "Can we starve cancer to death by eating?" He provided a new idea for treating related diseases by inhibiting angiogenesis. Although this research path is not smooth, compared with traditional "poisoning" cancer cell drugs, cutting off "food" is indeed a clever new strategy.

Angiogenesis, in simple terms, is the process of new blood vessel formation. Many researchers are committed to exploring how to control the growth of blood vessels in order to "starve" cancer cells and curb their destructive power. This concept is not limited to the field of cancer, but also shines in ophthalmic diseases. For example, in diseases such as wet AMD and diabetic retinopathy, inhibiting angiogenesis is also a key treatment strategy.

VEGF is a key factor in angiogenesis and plays an important role in the pathological process of wet AMD by promoting the formation of new blood vessels and increasing vascular permeability.
Currently, the FDA has approved a variety of anti-VEGF drugs for wet AMD, including Ranibizumab, Aflibercept, Bevacizumab, Brolucizumab, etc. These drugs effectively slow down the growth of new blood vessels by inhibiting the VEGF signaling pathway.

Among them, Regeneron's Aflibercept has sales of $9.4 billion in 2023 and is the best-selling innovative drug in the field of ophthalmology. The drug fuses the key regions of VEGF receptors 1 and 2 and combines with the Fc fragment of human immunoglobulin G1 (IgG1) to form a high-affinity fusion protein. It can simultaneously inhibit VEGF-A, VEGF-B and PlGF, thereby more comprehensively blocking abnormal angiogenesis and leakage.

As a landmark treatment in the field of ophthalmology, anti-VEGF drugs have brought good news to AMD patients, but they also have their limitations. For example, some wet AMD patients will experience diminishing returns after long-term anti-VEGF treatment, that is, the initial medication is effective, but as the treatment continues, the visual improvement gradually slows down or even recurs. Clinically, doctors often have to increase the frequency of medication or consider changing medications, which not only increases the medical burden on patients, but also highlights the limitations of the single-target strategy.

Moreover, VEGF drugs are fundamentally not a universal solution. Complex diseases often involve multiple pathological mechanisms, and single targeting strategies have limitations. In addition, individual differences among patients lead to significant variations in treatment responses and side effects.

Faced with this problem, the development of small molecule drugs and more comprehensive treatment options targeting multiple pathological pathways has become a new direction, which is expected to improve the overall efficacy and reduce the treatment pressure on patients.

Beyond VEGF, Small molecules enter the game, bringing new treatment opportunities

In recent years, multi-target drug research targeting angiogenesis and inflammation has brought new hope for the treatment of wet AMD and is expected to break through the limitations of traditional VEGF inhibitors. The treatment of wet AMD is moving from a single target (such as VEGF) to a diversified intervention strategy. In addition to traditional VEGF inhibitors, new targets targeting inflammation, angiogenesis and metabolism are constantly emerging. The figure below shows multiple potential pathways and their corresponding small molecule drugs under development, providing a reference for new treatment opportunities beyond VEGF.

Although small molecule drugs for wet AMD have not yet been approved for marketing, several drugs have shown potential in Phase I and Phase II clinical trials: GB-102, EYP-1901, AXT107, and UBX1325, etc. These drugs have different mechanisms of action, pharmacokinetics, and safety characteristics, and may be superior to existing anti-VEGF injection treatments in some aspects.

1. GB-102
GB-102 is a novel injectable depot formulation of the anti-tumor drug sunitinib malate that targets both VEGF-A and PDGF-BB. After intraocular injection, GB-102 forms a reservoir in the underlying vitreous body that is gradually biodegraded over time. Its advantage is that it has a longer treatment interval, which is of great significance in reducing the treatment burden on patients.

The ALTISSIMO (Phase IIb) study showed that compared with GB-102 administered once every 6 months and aflibercept administered once every 2 months, 48% of the subjects in the GB-102 group did not need additional supplementary treatment for at least 6 months, and 62% of the patients did not need additional supplementary treatment for at least 4 months; in addition, the degree of CSFT decline in the GB-102 group was similar to that in the aflibercept group, but the degree of BCVA improvement in the GB-102 group was worse than that in the aflibercept group. In view of the above results, the clinical trial was extended for 6 months to allow for a more comprehensive analysis of the trial results, thereby clarifying the development prospects of the drug.

2. EYP-1901
EYP-1901 uses EyePoint's proprietary sustained-release Durasert E technology to deliver vorolanib intraocularly. The active ingredient of the drug is vorolanib, a new generation of multi-target tyrosine kinase vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor, which intermittently inhibits PDGFR + VEGFR to effectively inhibit angiogenesis. Beida Pharmaceuticals' Class 1 innovative drug vorolanib tablets with the same active ingredient were approved for marketing on June 8 for the treatment of renal cancer.

EYP-1901 uses Durasert sustained-release drug delivery technology to enable voronib to be continuously released in the eye in a controllable and tolerable manner, extending the injection treatment cycle, improving patient treatment compliance, reducing medical burden, and ultimately improving patient clinical outcomes.

The DAVIO 2 study showed that both doses of EYP-1901 showed statistical non-inferiority in best corrected visual acuity (BCVA) compared to the active control group and performed well in terms of safety. Compared with the aflibercept control group, statistical non-inferiority was shown in BCVA change at weeks 28 and 32 combined. The 2mg and 3mg doses of EYP-1901 reduced the treatment burden by 89% and 85%; 65% and 64% of the eyes in the 2mg and 3mg doses of EYP-1901 groups did not require additional treatment for up to six months.

3. AXT107
AXT107 is a novel drug candidate based on type IV collagen-derived peptides that inhibits vascular leakage and neoangiogenesis by inhibiting VEGF-A and VEGF-C and activating Tie2, blocking the VEGF receptor signaling pathway.

Preclinical studies have shown that AXT107 has the potential to treat ischemic retinopathy and choroidal neovascularization, and can be administered once a year through a self-forming gel mechanism. The drug is currently in Phase I/IIa clinical trials to evaluate its safety, tolerability and efficacy, and has been approved by the FDA for the study of diabetic macular edema (DME) and wet age-related macular degeneration (AMD).

4. UBX1325
UBX1325 is a small molecule inhibitor of Bcl-xL, a protein that helps senescent cells survive. Currently, the drug is being studied clinically for wet AMD and diabetic macular edema (DME), and has shown positive efficacy in Phase II trials. UBX1325 is administered by intravitreal injection, once every 12 weeks or longer, depending on the patient's treatment response.
Future Outlook

The development of small molecule drugs has opened up a new path for the treatment of wet AMD. Through multi-target intervention, it can not only inhibit angiogenesis, but also regulate pathological links such as inflammation and oxidative stress. In addition, some drugs can achieve ultra-long-term drug delivery through the optimization of delivery technology, improve patient treatment compliance, reduce medical burden, and ultimately improve patient clinical outcomes.

Although many drugs are still in the early research or clinical trial stage, they show great potential and are exciting. With the deepening of basic research and the continuous emergence of innovative drugs, the precision treatment of wet AMD is ushering in a new dawn.

In conclusion, while discussing how to protect the health of our eyes, how can we integrate these scientific concepts into our daily lives in a humorous and practical way?

Laughter therapy, a two-pronged approach: Just as Liang Lingyi’s team found that laughter exercise has a significant effect in the study of dry eye disease, laughter can not only improve mental health, but also indirectly inhibit angiogenesis. Take a few minutes a day to laugh a few times and let laughter be your secret weapon in the fight against eye disease and cancer.

Diet fights cancer and eats healthily: William Li’s research reminds us that a reasonable diet can help “starve” cancer by inhibiting angiogenesis. Consume more antioxidant- and anti-inflammatory foods, such as blueberries, green tea, nuts, and dark green vegetables, which not only help prevent cancer but are also great for eye health.

Whether you relax by laughing or protect your body by eating healthy, let us use scientific methods and a happy mood to protect our eyes and overall health.

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