Release date:2023/11/30 10:33:30

Compared to areas such as oncology and autoimmune diseases, ophthalmic drug development started late but is growing rapidly. According to Global Market Insights, The global ophthalmic drugs market size was estimated at USD 33.4 billion in 2022 and is projected to reach USD 61.5 billion by 2032, growing at a CAGR of 6.3% during the forecast period from 2023 to 2032. [1]

In terms of clinical demand and development difficulty, myopia (delayed), dry eye, glaucoma and age-related macular degeneration (AMD) are among the key areas for ophthalmic innovative drugs. Here, we mainly introduce these ophthalmic disease drug development.

Intraocular Vascular Disease - Anti-VEGF Therapies

Among ophthalmic drugs, intraocular vascular disease therapeutics have the largest market share, and this segment is dominated by anti-vascular endothelial growth factor (VEGF) drugs. AMD (age-related macular degeneration) and DME (diabetic macular edema) are major causes of vision loss in the elderly. Anti-VEGF agents, with the effects of reducing retinal neovascularization (RNV) and choroidal neovascularization (CNV), and inhibiting vascular permeability, have revolutionized ocular neovascularization therapy. 

A range of anti-VEGF drugs is currently utilized in ophthalmology, including pegaptanib (Macugen), ranibizumab (Lucentis), aflibercept (Eylea), brolucizumab (Beovu) and faricimab (Vabysmo). According to their molecular modalities, these anti-VEGF agents can be divided into aptamers, monoclonal antibodies (mAbs), bispecific antibodies, and recombinant fusion proteins. 

Drug Name Trade Name Company Approval Year Type Indications
Pegaptanib Macugen Eyetech / Pfizer Inc 2004 Aptamer Wet-AMD
Ranibizumab Lucentis Roche/Novartis 2006 mAb Wet-AMD; DME; Diabetic Retinopathy; Myopic Choroidal Neovascularization
Aflibercept Eylea Regeneron/Bayer 2011 Fusion protein Wet-AMD; DME; Diabetic Retinopathy; Retinopathy of Prematurity
Brolucizumab Beovu Novartis 2019 mAb Wet-AMD; DME
Faricimab Vabysmo Roche 2022 Bispecific antibody Wet-AMD; DME; Retinal Vein Occlusion

Table 1. FDA approved anti-VEGF therapies for intraocular vascular disease

Aflibercept, a fusion protein-based anti-VEGF ophthalmic drug co-developed by Bayer and Regeneron, is currently the highest-selling anti-VEGF ophthalmic drug in the world, with 2022 sales of $9.647 billion (2023H1 revenue is $4.667 billion.) There are a total of six drugs with global sales of nearly $10 billion in 2022 (excluding COVID-19-related drugs), of which Aflibercept is the only non-oncology-related drug.

Faricimab (Vabysmo) was approved by the FDA in January 2022 for the treatment of macular edema caused by retinal vein occlusion (RVO), the world's first approved bispecific antibodies ophthalmic drug. In 2022, Vabysmo's sales reached $620 million;  in the first six months of 2023, Vabysmo already crossed the one-billion-dollar sales mark, having brought in 957 million Swiss francs ($1.1 billion) . 
Related Articles: 
Bispecific Antibodies - Current Status and Prospects

Geographic Atrophy Treatments - Complement Inhibitors

AMD can progress to an advanced degenerative stage manifesting as geographic atrophy (GA), characterized by irreversible vision loss due to loss of retinal pigment epithelium (RPE), photoreceptors and choriocapillaris in the macula.

Overactivity in the complement system leads to disease progression, and therefore, inhibiting the expression of this complement system is a new direction in the treatment of GA. Most of the GA-related drugs in development are still in the early stages of clinical development, with only two drugs approved by the FDA in 2023.

SYFOVRE (Pegcetacoplan), developed by Apellis, is a pegylated complement C3 inhibitor peptide approved by the FDA in February 2023 for GA. It is the first FDA-approved drug to treat GA.

Avacincaptad pegol (IZERVAY™; formerly Zimura®) is a complement C5 inhibitor that is being developed by IVERIC Bio. In August 2023, the FDA approved IZERVAY for the treatment of geographic atrophy secondary to AMD. 
Related Article: 
Geographic Atrophy Treatments Under Investigation

Chronic Dry Eye Disease

Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and subacute inflammation of the ocular surface.

Currently, treating dry eye disease involves using ocular surface lubricants, anti-ocular surface inflammatory drugs, punctual plugs to reduce tear loss, and eyelid therapy for meibomian gland restoration. However, these methods only lessen dry eye symptoms without complete elimination. Basic treatments like artificial tears, silicone shields, and lenses are common, but moderate-to-severe dry eye with surface inflammation requires essential anti-inflammatory and immunosuppressive treatments.

Cyclosporine ophthalmic formulations, used as symptom ameliorators, lead the dry eye market in sales, with $2.42 billion in 2020 ($5.24 billion in the dry eye market over the same period). One of the most prominent drugs is Restasis (cyclosporine), which was marketed in 2003 and was the world's first drug for the treatment of moderate-to-severe tear-deficient dry eye, with global sales of $1.29 billion in 2021.

Compared to artificial tears, cyclosporine eye drops are considered superior in treating dry eyes. Mechanistically, the mechanism of action of cyclosporine is clear. Cyclosporin A eye drops can inhibit the apoptosis of lacrimal gland follicular cells and conjunctival epithelial cells, promote the apoptosis of lymphocytes, inhibit the inflammatory reaction of the ocular surface, enhance the immune function of corneal cells, thus promoting the secretion of tears, and playing a role in the treatment of dry eyes. From the clinical point of view, cyclosporine is more effective. The treatment of dry eye by artificial tears is limited to relief, and there are several clinical results showing that cyclosporine A eye drops have better efficacy in the treatment of dry eye, and have a good safety profile.


Figure 1. Mechanisms of action of cyclosporine and effects on connective tissues. [3]

There are many dry eye drug targets in development, focusing on RASP (reactive aldehyde species), MCR (melanocortin receptor), and TNF (tumor necrosis factor) (Table 2).

Name Company Phase Type
Reproxalap Aldeyra NDA RASP inhibitor
PL-9643 Palatin III MCR agonists
CyclASol (SHR8058) Novaliq NDA Cyclosporin
Timbetasin (RGN-259) RegenaRx III Peptide
Tavilermide  (MIM-D3) Mimetogen III Tyrosine kinase TrkA receptor agonist
BRM421 BRIM Biotechnology III repairs corneal damage
Table 2.  Selected new dry eye drugs in late clinical stage

Aldeyra's Reproxalap, a First-in-class small molecule RASP inhibitor, aims to achieve therapeutic benefits by lowering levels of pro-inflammatory aldehydes. In February, the FDA had accepted its NDA, however, on October 16, reviewers concluded that Aldeyra needed to conduct additional clinical trials to meet efficacy requirements, leaving the future of Reproxalap's launch uncertain. On November 1, Aldeyra entered into an exclusive commercialization license in the U.S. with AbbVie, and Aldeyra is eligible to receive $300 million in regulatory and commercial milestone payments, of which $100 million is an upfront payment upon approval of Reproxalap.

Gene Therapy in Ophthalmology

Gene therapy refers to the introduction of normal genes into human cells to correct or supplement diseases caused by genetic defects and abnormalities, and is a fundamental strategy for treating genetic diseases. After 30 years of development, gene therapy has become a key tool in the treatment of various human genetic diseases. Adeno-associated virus (AAV) is considered to have a good safety profile due to its ability to infect a wide range of tissues and its low immunogenicity and low integrative capacity. Thus, AAV has become one of the most cutting-edge, promising and commonly used viral vectors in the field of in vivo gene therapy.

Eye diseases are ideal candidates for gene therapy. On the one hand, the eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation. On the other hand, many eye diseases are caused by defects in single or multiple genes, and many mutations in inherited eye diseases have been precisely identified, providing numerous target options for gene therapy development.

The current indications for ophthalmic gene therapy are mainly Inherited Retinal Diseases (IRDs) associated with mutations in a single gene, including retinitis pigmentosa, choroideremia, Leber Hereditary Optic Neuropathy (LHON), Leber Congenital Amaurosis (LCA), Stargardt's disease, Achromatopsia (ACHM), X-linked retinoschisis (XLRS), and age-related macular degeneration (AMD), etc.

In December 2017, the FDA approved Luxturna (Voretigene Neparvovec-rzyl), a gene therapy from Spark Therapeutics, for the treatment of inherited retinal diseases caused by mutations in the RPE65 gene. This is the first in vivo gene therapy to receive FDA approval, but the therapy also ranks in the list of the top 10 most expensive drugs in the world. Based on 2022 statistics, Luxturna will cost about $850,000 for treatment of both eyes with a single injection to achieve efficacy.


Figure 2. Luxturna, source:


In the future, the research of new ophthalmic drugs will make more use of new technology platforms. Small molecule chemotherapeutics, peptides, antibody fragments, RNAi therapy, cell therapy, gene editing, gene replacement therapy, etc., have the potential to produce significant advancements in drug development., adding more "light" to the world.

[2] Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013;120(1):106-114. doi:10.1016/j.ophtha.2012.07.038 
[3] Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clinical Investigation. 2015;5(3):267-285. DOI: 10.4155/cli.14.135. PMID: 25960865; PMCID: PMC4420022.

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