GV-971 – A novel multi-target drug for the prevention and treatment of Alzheimer's disease, leading the new direction of international AD drug research

For the prevention and treatment of neurodegenerative diseases, Green Valley has built up a series of leading research platform including pharmacological platform focused on neurodegenerative disease common pathogenesis , neurodegenerative diseases related biomarkers research and development platform, as well as an unique platform for drug screening and research.

2018-06-19

Since the beginning of the new century, competition among great powers across the world in the field of scientific research have been focused on the frontier of innovative technology about the final mystery of human body, i.e. the brain including its  normal cognition, aging and disorders. Governments worldwide have invested huge sums of money in brain related initiatives. However, this “three-pound matter lying between the two ears” is still a relative "black hole" of human understanding, and is dubbed as a "Three-Pound Universe". Brain science is regarded as the “Final Frontier” of human understanding of natural phenomena and the human body. The scientific community even calls neuroscience – the science of studying the human brain – as the "last frontier of human science". Due to the lack of understanding about the human brain, neuropsychiatric diseases caused by brain disorders have led to huge economic and social burdens , much more than any other disease. As a neurodegenerative disease with progressive brain damages and the highest incidence, Alzheimer's disease (AD) has caused great suffering to patients. There are 47 million patients with dementia worldwide, and for every 69 seconds, 1 patient is diagnosed with AD. China has the largest number of patients with dementia accounting for up to 1/4 of the global patients suffering from dementia With the aging of population, the growth rate of patients with dementia in China is twice that of developed countries. However, as yet, there are no drugs that can cure this disease, and the commercially available drugs can only help alleviate the symptoms of the patients. In this sense, given no drug available to cure, delay or modify the progression of AD, the number of patients with dementia is estimated to reach 135 million globally by 2050. Therefore, R&D of novel anti-AD drugs has come up as a strategic issue associated with sustainable social development. Futhermore , it not only represents the unmet demand of , the pharmaceutical market, but also that of the huge number of patients in the 21st century.

AD isn’t a disease associated with a single protein or a single gene. Rather, it is  a complex disease affected by the cascading amplification of multiple factors, such as misfolding of proteins, damage to cholinergic neurons, oxidative stress and inflammatory reactions. As the human body is a complex, yet precise and robust system, many complex diseases are not induced by a single factor but involve the synergies of many factors. Therefore, the limitations of research ideas and methods based on "reductionism" are increasingly heightened. The simple assumption of a complex disease model based on "reductionism", a typical representative of which is AD, is also facing severe challenges. With rapid development of life science and modern technology in recent years, more and more studies have found that single target therapy is insufficient to really modify the process of AD – a complex disease, while multi-target and synergistic therapy are the effective strategies and direction for the treatment of AD.

GV-971 developed by Green Valley, is a novel drug for the prevention and treatment of Alzheimer's disease. The drug is protected by global intellectual property rights. Research results have shown that GV-971 targets multiple Alzheimer's disease etiologies. First, GV-971 targets β-amyloid (Aβ), the main factor causing AD in the brain. During this process, GV-971 concurrently inhibits Aβ aggregation and disperses preformed Aβ aggregates. Studies have shown that GV-971 plays an important role in the treatment of AD, such as, alleviating neuroinflammation, regulating the homeostasis of neurotransmitters, and improving cognitive impairment and behavioral and psychological disorders. Phase I and II clinical studies have demonstrated that it is safe and has shown a good tendency to improve cognitive impairment. When the results of phase II clinical trials were presented in the form of a special oral report at the 7th Global Alzheimer's Clinical Research Conference 2014 in Philadelphia, GV-971 won high praise from international expert, who believe that "the prospective targeting concept and the first-ever multi-target research and development strategy proposed by Chinese scientists would surely lead international research on anti-AD drugs."

For the prevention and treatment of neurodegenerative diseases, Green Valley has built up a series of leading research platform including pharmacological platform focused on neurodegenerative disease common pathogenesis , neurodegenerative diseases related biomarkers research and development platform, as well as an unique platform for drug screening and research.

(1) Drug screening and evaluation platform for neurodegenerative diseases

In view of the common characteristics of abnormal folding and aggregation of proteins in neurodegenerative diseases, a three-dimensional screening system integrating the binding properties of protein, protection function of neurons and the permeability of blood-brain barrier has been established based on the SPR-based protein chip screening technology. A system for the research on the mechanism of actions (MOA) of candidate drugs has been set up using computer-aided design, carbohydrate affinity chromatography and proteomics technology, combined with scanning electron microscopy, circular dichroism spectra, molecular and cellular biology as well as neuropharmacology. APP/PS1 and 5X FAD transgenic animal models that can mimic the clinical features of AD were used to evaluate the effects of candidate drugs on learning and memory functions and mental state using behavioral evaluation technology platform. The changes and associations among animal behaviors, brain waves and chemical substances in brain were observed using real-time monitoring system. The pathological and morphological parameters of biological tissues were provided using the molecular imaging system, combined with the immunohistochemistry experimental system. The drug-disease model reaction database was built by integrating behaviors, chemical substances, histopathology and other data, to provide data support for clinical drug use. In addition, all the above data were used to modeling and explore the regulatory pathway (network) and regulatory mechanisms of the onset and development of nervous system diseases, and further using the positive drugs as probes to discover new drug targets and to do the functional validation. Through the integration and improvement of existing R & D technology, combined with the development of relevant technical systems, a relatively complete technology platform for screening and evaluating new anti-neurodegenerative disease drugs has been established.

(2)Biomarker clinical detection and monitoring platform

In view of existing biomarkers, a panoramic omics analysis platform combining proteomics, transcriptomics, metabonomics and exosome metabonomics was applied to build a biomarkers-based comprehensive technical platform, integrating clinical diagnosis and drug efficacy monitoring. Taking AD as an example, at present, biomarkers used for the diagnosis of AD and the determination of drug efficacy include imaging and non-imaging markers. Non-imaging markers mainly include Aβ and Tau in cerebrospinal fluid. However, the technique for collection of cerebrospinal fluid is invasive and very hard to implement. The latest research shows that some exosomes in peripheral blood are derived from brain tissues and contain Aβ, Tau, P-Tau and other components of brain tissues, and are related to the contents of these components in brain tissues. Therefore, the contents of Aβ, Tau and P-Tau in peripheral blood exosomes derived from brain tissues are used as the auxiliary indices to judge whether a patient suffers from AD as well as the severity of the disease, and the objective index of drug efficacy. Imaging markers mainly include Aβ –PET and Tau-PET, which are used for the determination of Aβ and Tau contents in brain tissues, as well as MRI and FDG-PET, which are used to test brain structure or functions.

Currently, imaging markers have been fully applied in the diagnosis of AD and clinical trials of drugs in overseas. Non-image markers have also been promoted extensively, but standards and the application in large scale have yet to be achieved.  In contrast , both imaging markers and non-imaging markers have not been developed in China, and it will take some time to catch up with the international level. In this project, a related biomarker detection technology system and biological sample library were established through clinical detection and research of AD-related biomarkers, to build a biomarker-based clinical detection platform. The construction of the platform is ensuring the development of relevant AD diagnosis standards and their extensive application. It is providing technical standards for the diagnosis of AD and clinical trials of AD drugs, thereby ensuring China retains competitive advantages and is a leader in the field of AD research, and will continue to lead international frontiers even after the project is completed.

(3) Unique platform for drug screening and research

The Green Valley Research Institute has built up an unique screening and research system based on in-depth studies on the MOA of drugs for the treatment of complex diseases, including Alzheimer's disease, Parkinson's disease, tumors, cardiovascular and cerebrovascular diseases using specific carbohydrate drugs as the screening targets prioritizing the capability and  feasibility of complex drug systems.

The successful development of GV-971 has filled the gap that has existed in this field for nearly 20 years. With considerable competitiveness and promising market prospects ,it has the potential to become a "blockbuster" drug not only in China but also in the international community, The annual sales volume is expected to exceed US$10 billion, which will have great social and economic significance. Its innovative mode of action and unique multi-target role provide a new perspective for the research and development of anti-AD drugs and a new understanding of the pathogenesis of AD. GV-971 is of great significance in promoting China’s international status in the field of innovative drug research.