Age-related macular degeneration is one of the leading causes of visual blindness in the elderly

Age-related macular degeneration (AMD) is an age-related structural change in the macula and is an irreversible disease that leads to progressive loss of central vision. AMD mostly occurs in people over the age of 50. In the past decade, it has affected about 30% of the middle-aged and elderly people in the world, and it is the first major blindness in the middle-aged and elderly people.

AMD can be divided into wet and dry. Wet AMD, also known as vascular exudative AMD, is characterized by abnormal growth of blood vessels and the infiltration of fluid and blood into the macula, which is responsible for central vision. Abnormal growth of new blood vessels behind the retina in the macular area is fragile and prone to bleeding and fluid. The leakage causes macular edema to bulge, creating damage to the macula. Dry AMD, ie without exudates and neovascularization, usually involves both eyes and is characterized by subchoroidal drusen deposition and geographic atrophy.

Dry AMD patients account for 80% to 90% of the total AMD patients. The most common symptoms of mid-term dry AMD are mild blurred or deformed vision. It can progress to wet AMD or geographic atrophy in later stages, resulting in severe visual impairment. People with advanced AMD generally experience increased stress in their lives, including an increased risk of functional impairment, such as falls or other injuries. At the same time, advanced AMD, especially atrophic dry AMD, increases the risk of cognitive impairment, such as Alzheimer's disease. More seriously, depression is common in advanced AMD patients. However, there is currently no effective drug for dry AMD that can stop the progression of the disease.

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There is no cure for dry AMD, the patient base and disease burden are huge, and the future market has great potential

1. There is no effective treatment for dry AMD

Advanced AMD, whether in the form of geographic atrophy or neovascularization, is a very common cause of severe vision loss worldwide. Patients with early and mid-stage AMD are at risk of progression to advanced AMD, and patients in the mid-stage AMD stage have a significantly higher risk of progression to advanced stage. Therefore, AMD must be treated as early as possible to stop disease progression and maximize patient outcomes. At present, there is no effective drug in the world to prevent the progression of dry AMD, and there is no effective treatment for advanced dry AMD with geographic atrophy, resulting in serious disease consequences such as vision loss. The progressive and irreversible nature of dry AMD has greatly increased the social cost burden, and the huge patient demand makes the drugs for the treatment of dry AMD have broad market prospects.

2. A large number of AMD patients

The global prevalence of AMD is about 8.7%. In 2020, there are about 196 million AMD patients worldwide. It is expected that the global AMD patients will increase to 288 million by 2040, of which Asian cases will reach 113 million. The global cost of vision impairment from AMD is estimated to exceed $300 billion, including more than $250 billion in direct healthcare costs.

Source: Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106-16. doi: 10.1016/S2214-109X (13)70145-1

3. Aging trends are increasing patient demand

Aging is a major risk factor for AMD progression, with nearly all cases of advanced AMD occurring in people over the age of 60. The study showed that the prevalence of advanced AMD in people aged 55-64 was about 0.2%, and it increased to 13.1% in people over the age of 85. China, the most populous country in the world, is experiencing the fastest ageing trend of any developing country, with 13.2% of the population over the age of 65 in 2020. It is expected that by 2025 and 2030, China's population over the age of 65 will reach 241 million and 309 million, respectively, with a compound annual growth rate of 5.4% and 5.1% from 2020 to 2025 and 2025 to 2030, respectively. Survey data show that the prevalence of AMD in China is increasing year by year, and is currently increasing at a rate of 15.5%.

Source: NBSC, Sullivan analysis

4. Favorable policies for ophthalmology promote the rapid development of AMD innovative drugs

In July 2019, the State Council promulgated the Healthy China Action (2019-2030), paying attention to the healthy development of the ophthalmology industry. In October 2016, the National Health and Family Planning Commission formulated the "13th Five-Year" National Eye Health Plan (2016-2020) to promote the cause of eye health and further improve the eye health of the people, reflecting the country's policy on age-related eye diseases, metabolic The importance of ophthalmological diseases such as STDs and the demand for ophthalmic resources. At the same time, the state encourages drug innovation and policies such as drug reform will continue to promote the research and development, review and approval of innovative ophthalmic drugs. It is expected that in the near future, there will be no cure for dry macular degeneration.

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The global competitive landscape of dry AMD under research --- research and development is difficult, and breakthrough innovation mechanisms are urgently needed to meet the huge clinical needs of patients

1. Global and domestic listed AMD drugs

At present, the AMD drugs on the global and domestic market are all aimed at wet AMD. The etiology of wet AMD is complex, but it is mainly characterized by choroidal neovascularization. The current treatment market is dominated by VEGF inhibitors, which are all administered by intravitreal injection or intravenous injection. Anti-VEGF drugs have become the main treatment drugs for retinal neovascular diseases including wet AMD, occupying more than 95% of the global market share. In 2006, the FDA approved the first anti-VEGF ranibizumab for AMD treatment. By 2020, the global sales of VEGF monoclonal antibodies in the field of ophthalmic disease indications will reach US$11.73 billion. Dry AMD accounts for more than 80% of all AMD, but there is currently no drug approved for dry AMD in the world, which is a market with great growth potential in the field of ophthalmic treatment.

2. The mechanism of action of dry AMD has not been clarified, and drug development is difficult

Dry AMD is a multifactorial disease, including genetic polymorphisms and external risk factors including age, smoking, obesity, high blood lipids, low physical activity, alcohol consumption, etc. Its mechanism of action has not been clear, so dry AMD The development of AMD drugs is extremely difficult.

Currently, the drugs for dry AMD currently in the global clinical development stage are all aimed at slowing the deterioration of the disease, mainly targeting the complement system, oxidative stress, and inflammatory response-related mechanisms. The most popular mechanism at present is called complement theory, which is mainly due to the activation of a large number of complement and its inhibitory factors at the lesion site, accompanied by the activation of other inflammatory mediators such as IL1-β, IL-18 and other cytokines. However, there is no effective clinical data to show that drugs targeting anti-complement, antioxidant, and anti-inflammatory mechanisms can prevent the course of dry AMD.

There have been many clinical trials based on complement theory in the past that have failed: Lampalizumab, a complement factor D inhibitor from Roche Group member Genentech, a phase III clinical trial of Lampalizumab treatment secondary to AMD with geographic atrophy (GA) in 2018 year declared a failure. The drug did not reduce changes in GA lesion size compared with "sham treatment." Alexion's Eculizumab, a complement protein C5b inhibitor, was proven to have no significant improvement in clinical trials, and failed a phase II trial in 2017. ACU-4429 is a dry AMD drug developed by Otsuka Pharmaceutical and Acucela® based on an anti-inflammatory mechanism. After eight years of clinical trials, it was declared a failure in 2016. Oral ACU-4429 failed in Phase III clinical trials. Prove it works. Drug development based on anti-complement and anti-inflammatory mechanisms has not yielded valid clinical data, so other pathogenic mechanisms may exist in dry AMD.

There is current research evidence that there are differences in the taxonomic and functional characteristics of the ocular microbiome in patients with dry AMD and healthy individuals, bacteria may be associated with the pathogenesis and progression of AMD, and specific bacterial categories can be used as potential biomarkers for AMD diagnosis. A study in Cell Discovery examined samples from patients with AMD. The analysis showed that the intraocular microbial community of AMD patients was significantly different from that of negative controls, and intraocular bacteria were present in AMD patient samples (Figure 4). Antibacterial methods can reduce the antigens that cause immune responses, and dry AMD drugs targeting the bacterial mechanism of action have become an innovative exploration path.

Source: Identification of an intraocular microbiota. Cell Discov. 2021 Mar 9;7(1):13. doi: 10.1038/s41421-021-00245-6.

3. Global competitive landscape of drug candidates for dry AMD

Complement and inflammatory mechanisms are still the main drugs under development in the world for dry AMD. There are only two products under development in China, both from Zhuhai Qi Microbial Technology Co., Ltd. (“Zhuhai Qiwei”). Zhuhai Qiwei is a subsidiary of Guangzhou Yinming Biomedical Technology Co., Ltd.

Based on its breakthrough scientific discovery on the etiology of AMD, Zhuhai Qiwei independently developed two treatments for dry AMD, QA102 and QA108. Unlike other investigational drugs that are anti-inflammatory by inhibiting complement, Zhuhai Qiwei's dry AMD drug uses a novel antibacterial treatment, mainly by inhibiting the bacteria in the immune response. The small-molecule oral drug QA102 is the first new drug for dry AMD with 'first-in-class' potential developed by a Chinese company that has been approved by the FDA for clinical trials. good security. TCM Compound Granules QA108 is also based on the antibacterial mechanism. It is the world's first TCM product for the treatment of AMD, and also the first product in China that has successfully obtained Phase II clinical trial approval for a new TCM drug in the category of 1.1 for the treatment of dry AMD. In the near future, the two products, QA102 and QA108, may provide new treatment options for intermediate and advanced dry AMD, bringing new hope.

Note: The research information is as of December 2021, excluding stem cell therapy.