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Wet AMD, an unmet medical need that can benefit from the discovery of novel small molecules

November 24, 2017

Age-related macular degeneration (AMD) is a common eye condition that causes damage to the macula, which is a small light-sensitive area located at the back of the eye that is critical for central vision. AMD is responsible for a blurred vision in the early stage of the disease but, ultimately, leads to blindness. It is estimated that AMD accounts for about 10% of all blindness worldwide and is the most common cause of blindness in developed countries.[1] Since the strongest risk factor or this disease is age, its prevalence is bound to increase with the current exponential ageing population. Hence, it is estimated that, by 2020, 196 million people will be affected by AMD and that this number will raise to 288 million by 2040.[1]

 

There are 2 types of AMD: the non-neovascular AMD (also called dry AMD or non-exudative AMD) and the neovascular AMD (also called wet AMD or exudative AMD); knowing that neovascularization means natural formation of new blood vessels. Although wet AMD accounts for only 10% to 20% of AMD cases, it causes the majority of instances with severe vision loss.[2] Wet AMD is caused by abnormal growth of blood vessels into the retina leading to leakage of blood and proteins causing damage to the eye’s photo-receptors. The wet AMD segment dominates the AMD market and is expected to reach more than US$ 8 billion by 2020.[3],[4]

 

The treatment of wet AMD has been revolutionized by the discovery of vascular endothelial growth factor (VEGF), which is a signalling protein that regulates the growth of new blood vessels. Anti-VEGF drugs have been recently developed to help stop neovascularization and preserve vision for AMD patients. However, the current wet AMD treatments only block the progression of the disease and do not reverse the symptoms. Additionally, all the currently marketed anti-VEGF drugs are large molecules (biologics, antibody fragments or protein-derived molecules) that are delivered by intravitreal (in-the-eye) injection. Not only this poses a financial burden, but the adherence to the treatment is poor.[5]

The main current pharmacological therapies for wet AMD are:

  • Ranibizumab (Lucentis, developed by Genentech, marketed in the US by Genentech and elsewhere by Novartis), a monoclonal antibody fragment (Fab) that targets VEGF-A. It is delivered by intravitreal injection and was approved by the FDA in 2006. By 2012, the wet AMD market was dominated by Ranibizumab, which accounted for 94% of wet AMD sales and by that time, this drug had generated US$ 11.95 billion in revenues since it was first launched.[3]

 

  • Bevacizumab (Avastin from Genentech), a VEGF-A humanized antibody delivered by intravitreal injection. Bevacizumab was FDA approved in 2014 for several cancers and was then also used to treat wet AMD.

 

  • Pegaptanib (Macugen from Eyetech/Pfizer), an aptamer (i.e. a single strand of nucleic acids) antagonist approved in 2004 which is also delivered by eye injection.

 

It is now recognized that there is a need to identify alternative treatments that rely on oral or topical (i.e. eye drops) delivery and/or that target other biological pathways. In addition, the discovery of novel small molecules can have a dramatic impact on the management of wet AMD. The novel treatments that are currently in development have been reviewed in the literature at several occasions,[6],[7] however, it appears clear that this is an area where lots of additional work can be done.

 

At Calixor Pharma Consulting, we are currently in discussion with a Singapore-based academic group that has discovered interesting novel small molecules that displayed efficacy in an in vivo mouse model. Please feel free to contact us if you would like to know more about this early stage drug discovery programme.

 

 

 

[1] Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis; Wong, W. L. et al. Lancet Glob. Health 2014, 2, e106-116.

 

[2] Current advances in the treatment of neovascular age-related macular degeneration; Villegas, V. M. et al. Expert Opin. Drug Deliv. 2017, 14, 273-282.

 

[3] Wet AMD market; Basharut, A. S. et al. Nat. Rev. Drug Discov. 2012, 11, 827-828.

 

[4] Global age-related macular degeneration market 2016-2020; Report from Technavio, 2016.

 

[5] The future of treatment for wet AMD; Desai, S. J. et al. Curr. Ophthalmol. Rep. 2017, 5, 93-97.

 

[6] Pharmacologic treatment of wet type age-related macular degeneration; Current and evolving therapies; Shams Najafabadi, H. et al. Arch. Iran. Med. 2017, 8, 525-537.

 

[7] Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration; Hussain, R. M. et al. Expert Opin. Emerg. Drugs 2017, 3, 235-246.

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