An overview of the development of drugs for age-related macular degeneration (2)

Author: the sea embraces all rivers In, we provide an overview of the AMD market and the status of marketed drugs In the future, there will be 300 million amd patients in the world and 40 million in China Under the huge unsatisfied demand, the market of AMD is growing rapidly VEGF drugs have become the first-line treatment drugs, while domestic arbacip, conbercept and rapunzumab are in a tripartite confrontation In this paper, the development and distribution of drugs, the distribution of companies, the distribution of targets, the development trend of technology and representative drugs are summarized It is hoped that this paper can be helpful for the research in this field It can be seen from the varieties on the market that AMD is a market dominated by biological drugs, and the distribution of varieties under research is no exception Biological drugs have entered the BLA stage due to their relatively high proportion of analogues and rapid progress, but there are also a few varieties that have been terminated and have not progressed (the next part of this middle part will be explained in detail) Although the cost of R & D, production and transportation of macromolecules is high, and the permeability of macromolecules is lower than that of micromolecules, it seems that for tumor specific targets or diseases with anatomically relatively isolated organs, the unique tissue distribution of macromolecules, such as only distributed in plasma and extracellular body fluids, better targeting selectivity, and relatively low side effects, often have advantages Source: drug delivery data, as of October 23, 2019, including biological analogues of rapunzumab and abacept Novartis now has a wide range of products on the market, including leizhumab, vitipofen, anecta and the newly launched brolucizumab Since 2008-2011, it has spent 52 billion US dollars to acquire elkon into the field of layout ophthalmology Now it has been galloping in the battlefield for many years It is an industry benchmark in terms of technology, quantity and quality, and it can be called the top player of AMD Roche and Genentech have jointly developed rapacizumab on the basis of bevacizumab In order to maintain high pricing, bevacizumab has not been promoted to ophthalmology, but the use of super tags is very common in the United States, once occupying a high market share Roche also has a number of high-quality clinical varieties, mainly biological drugs, the most famous is fariimab Bayer, Zaiyuan and towering United have led amd market for many years by virtue of abecept In recent years, Pfizer has become more and more popular in the field of tumor and immunity, and its ophthalmic performance is comparable to Novartis and Roche, but the majority of chemical drugs, slow progress and poor overall performance Layout of AMD drug R & D company Source: drug delivery data, as of October 23, 2019, including drugs in all stages and states The research and development of AMD in China is relatively late, but conbercept has performed well New drugs under research in China are mainly biological drugs Enterprises rely on independent research and development, cooperation or subsidiary layout Conbercept, the leading variety of Kanghong pharmaceutical, has been on the market for many years Now, three indications have been approved and it is about to open up overseas market Rongchang biology has all human fusion protein in hand, Suzhou Stanville biology has complete antibody Xinda biology has a prospective layout in target and technology The VEGF / complement bispecific antibody developed by the fit LG platform of Anmai has entered the clinical practice Beida entered the market by purchasing Kanan Jihua medicine cm-082, and now it has entered the third phase of clinical practice Xiansheng pharmaceutical and Jiangsu Taikang introduced a monoclonal antibody from epitomics Xiansheng is mainly in the direction of tumor, and Taikang is responsible for the development of ophthalmic diseases The McAb developed by Dongyao has granted China's rights and interests to Li's pharmaceutical factory Kaikai Pharmaceutical Co., Ltd has also cooperated with Pfizer on an ALK drug, which is mainly used for tumors The all human fusion protein of Huabo biology, a subsidiary of Huahai pharmaceutical, has also entered clinical practice List of class 1 amd drugs in China Source: Yaodu data, as of October 23, 2019 At present, there are not many kinds of innovative drugs entering BLA stage and phase III of AMD, and some of them are terminated because their efficacy is not as good as the drugs on the market, as shown in the table below Abicipar pegol is an anchor protein replication protein developed by Elgin It is injected intravitreal every three months, and Bla has been submitted to the European Union and the United States Roche's two biological drugs have entered the third phase Fariimab is a brilliant humanized bispecific antibody of Leizhu mAb Lampalizumab is a monoclonal antibody In 2018, the phase III trial named Mako was unblinded The test results showed that it did not reach the main end point, and the efficacy was not as good as that of rajeumab There are many new target drugs, such as RPE65 related drugs, complement C3 and C5 inhibitors Although there are few ophthalmic researches on C5, there are about 20 kinds of C5 developed in urogenital diseases such as whole sleep hemoglobinuria, including 2 listed varieties C3 clinical R & D is less than 10 List of non-1 amd drugs that have entered BLA and phase III in the highest R & D stage In terms of overall target layout, VEGF is still the main target, even though it does not include biological analogues, while anti angiogenic drugs are the main research direction, including PDGF and other related targets The distribution of biological drug targets is more concentrated, and the molecular typing of chemical drugs is more In addition to the complement system mentioned above, the proportion of chemokines and integrins is also high This article simply lists the targets, and then introduces the innovation potential of the targets and the distribution of the main treatment areas in detail We will discuss with you which potential new targets are in the field of AMD Distribution of chemical target Distribution of biological drug targets Source: drug delivery data, as of October 23, 2019, remark: the uncertain target and biological analogues have been removed, including the determined preclinical drugs, and the multi-target drugs have been calculated separately Now the treatment of AMD has entered the next milestone stage, whether in terms of efficacy or frequency of administration, but it has not yet jumped out of the barriers of low compliance and high recurrence rate (more than 50%) caused by vitreous injection and high price The approved drugs are mainly for wet AMD, while the number of dry amd patients is large, if not treated in time, it will increase the difficulty of follow-up treatment, so this territory also needs to be developed From the perspective of mechanism, the existing research shows that VEGF is only one of the factors that cause blindness in AMD In the future, more researches are needed to explore the related target mechanism Therefore, there are still huge unmet clinical needs in AMD Combing all the drugs under research, we found that they were mainly concentrated in four directions: 1 Biological analogues solve the problem of economic benefits; 2 To improve the administration system, administration frequency, dosage and efficacy of the drugs with VEGF as the main direction, such as changing from vitreous injection to long-acting microsphere implant, combining with other target drugs such as PDGFB inhibitors, developing compound preparations, or combining with new external auxiliary eye drops; 3 Develop new target and new technology drugs, such as TF (tissue factor) drugs and gene therapy; 4 Develop drugs for dry AMD, such as drugs targeting complement system and oxidative stress-related mechanisms At present, the global R & D enthusiasm of razumab analogues is high, and more than ten varieties have entered the clinical stage, among which razumab ® has been listed in 2015 There are relatively few appicip analogues under study This is mainly related to the time to market of the drug In addition, from the technical point of view, for enterprises that produce analogues, Leizhu mAb and brolucizumab are humanized antibodies that only need to be expressed in E Although there are no bioanalogues of rapunzumab and arbacicept in China, many of them have been used in clinical practice In the third phase of Lei Zhu McAb, Kangqiao capital introduced varieties from Samsung bioepis, and Qilu and biocnd cooperated varieties In addition, the varieties of Shanghai United sail, Fudan Zhangjiang, Sansheng Guojian and baiaotai are in phase I The biological analogue Qilu of abacepu has entered phase III, while Shandong Boan and LVYE pharmaceutical are in phase I In the future, Qilu is expected to seize the domestic Wamd market with biological analogues Aflibercept / nesvacumab is a compound of VEGFA / PGF and Ang-2 inhibitors, which was developed by regenerator and authorized to Bayer It is currently in the phase II clinical trial for the treatment of diabetic macular edema and wet age-related macular degeneration However, the compound of arbacicept / rinucumab (PDGFR antagonist) has been terminated in phase II clinical practice The combination of rapunzumab and peggeranib Stadium (1.5 mg), an inhibitor of PDGFB, has entered the clinical phase III A phase II clinical trial showed that the combination significantly improved visual acuity (10.6 vs 6.5 letters) compared with razumab Peggeranib stadium was initially developed by archemix and eyetech pharmaceuticals (a subsidiary of OSI eyetech, OSI pharmaceuticals), and then authorized to opphotech and Novartis to treat AMD New topical eye drops have been developed to reduce the frequency of vitreous injection and increase the efficacy, such as clinical phase II small molecule eye drops: VEGFR2 inhibitor pan-90806 and itgav & ITGB3 antagonist sf-0166 The compliance of patients with multiple intravitreal injections is low, and the permeability is obviously insufficient Currently, ksi-301 is the drug with optimized administration times This is Kodiak using its ABC Gamma The biological preparation developed by the platform is in phase II clinical control with abacetin It is designed to be administered every 12, 16 and 20 weeks The trial started in early September The performance of sunitinib targeting VEGFR and other drugs in renal cell carcinoma is obvious to all At present, this old drug is emerging in the field of Ophthalmology through preparation improvement Gb-102 developed by graybug vision is a long-acting microsphere implant of sunitinib, which is implanted into the vitreous cavity to control the slow release of the drug The existing data shows that patients using gb-102 are still effective after 3 months or 6 months of administration, and the phase II clinical control with abacept has been carried out in October 2019, with an interval of 6 months As an anatomically isolated organ, the risk of gene therapy is relatively low With the further application of adenovirus and lentivirus, gene therapy for hereditary retinal diseases has been listed Although AMD is a multifactorial disease, the strategy of targeting VEGF to alleviate disease blindness once and for all has also been preliminarily verified For example, rgx-314, a phase II variety, is a gene therapy with NAV AAV8 vector developed by regenxbio, which can encode anti VEGF antibody fragments, thus repairing the neovascular leakage pathway leading to retinal effusion and vision loss Oxb-201 is also a gene therapy in phase I TF (tissue factor) is the receptor and catalytic cofactor of coagulation factor VII or VIIa It can form complex with TF to activate coagulation factor X and start external coagulation At present, the target research is still in the early stage, with few drugs in research, mainly used for solid tumors and ophthalmic diseases The representative drug for ophthalmology is icon-1 This is a bifunctional immune protein, including the guiding sequence composed of the mutant inactivated clotting factor VIIa and the effect sequence composed of the Fc fragment of IgG At present, the drug is being compared with rajeumab or sham injection, and a phase II clinical trial has been completed, and another is in progress The first drugs used for dry AMD, such as β - carotene, are rarely used to restore vision as an auxiliary treatment Among the new therapeutic drugs under development, avacintaptadpegol, a complement C5 inhibitor, pegcetacopolan, a complement C3 inhibitor, and alk-001, a micronutrient a analogue, have entered phase III clinical trials