【Chronic HCV infection background】
Chronic Hepatitis C (HCV) is one of the most common serious liver infections in the world. HCV is extremely dangerous and is a major cause of liver cirrhosis and liver cancer. The global distribution of HCV infection is complicated. The World Health Organization (WHO) estimates that around 130 million to 150 million people worldwide are chronically infected with HCV, including about 13.9 million in China. In China, there are still a large number of infected people who fail to receive effective treatment due to factors such as low detection rate, low diagnosis rate, and complicated distribution of infected people. Therefore, the HCV market in China is of great potentials.
Traditional interferon (IFN) therapy and the direct antiviral combination therapy used in recent years are effective treatments for HCV. As the clinical treatments progress, people gradually found that IFN therapy could not be effective for all patients under the influence of factors such as differences in gene types of HCV and degrees of cirrhosis. Statistics shows that the whole cure rate of IFV+RBV therapy for HCV is only 50%-60%, while the rate of direct antiviral combination can reach above 90% and some combination cure rate is close to 100%. Besides this, IFN therapy has more side effects and spends more time in treatment cycle (48 weeks) when it is compared with direct antivirals (only 12 to 24 weeks). Thus the direct antiviral combination therapy has gradually replaced the traditional IFN therapy, and currently the protease (NS3/4A), replicase (NS5B) and replication complex protein (NS5A) are the known direct targets of antiviral drugs.
Seraprevir is a second generation protease (NS3/4A) inhibitor developed independently by Ginkgo. This drug was granted patent authorization in December 2014 (patent number: ZL201210034872.0). By far it has successively completed the foreign PCT applications (application number: PCT/ CN2012/085912) and obtained the patent authorization of the United States & Japan (patent number: US14/375.418; JP2014-556905).
Presently, Ginkgo is working on the following two direct antiviral combinations:
Project 1: Seraprevir (NS3/4A) + Sofosubuvir (NS5B)
The results of phase II clinical trials shows that this combination has the same effect as the imported drug, and the subjects are well tolerant to this drug. Seraprevir is expected to complete clinical studies in phase III by the end of 2019 and will apply for NDA in 2019.
Project 2: Seraprevir (NS3/4A) + Replication complex protein (NS5A)
This combination consists of two domestic new drugs in first sorts and owns completely independent intellectual property rights. Clinical trials have shown that the combination is expected to be as effective as imported products and has the advantages of safety and far lower incidence of AE than IFN therapy. The combination is expected to apply for NDA in 2020.
Influenza is a viral infection that mainly affects the nose, throat, bronchus, and lungs. The infections usually last about a week, and most people recover within 1 or 2 weeks without any medical treatment. However, the infection could bring serious complications, pneumonia and even death to the young children, aged people and people who have other symptoms.
According to WHO, every year about 1 billion cases of influenza occur globally. Meanwhile, the seasonal influenza brings serious complications for around 5 million people, and approximately 290,000 to 650,000 people die from the infection.
China is also in face of a severe situation of influenza. Statistics from the Chinese Center for Disease Control and Prevention (CDC) show that the number of cases of seasonal influenza in China was 457,000 in 2017, but in the first half of 2018, the number increased rapidly and reached to around 556,000. Moreover, China's flu market is emerging because of a lack of treatment options and rising domestic demand for more anti-flu drugs.
Two main classes of drug interfere with influenza virus infection which are used for prevention and treatment in clinic are the M2 ion channel blocker and the viral neuraminidase (NA) inhibitors, and NA inhibitors have occupied a large share of the current influenza market.
The main components of M2 ion-channel inhibitors are Amantadine and Rimantadine, and the influenza virus could easily develop rapid and widespread drug resistance to these drugs. Besides this, these drugs also have shortcomings such as inefficacy against type B virus and limited scope of drug use.
The main representatives of NA inhibitors are Zanamivir, Oseltamivir, Peramivir and Laninamivir, which have the advantages of inhibiting the replication of influenza virus and reducing the symptoms of influenza. However, the side effects and drug resistance of these drugs limit its use, not only in patients infected with influenza beyond 48 hours, but also in patients with severe symptoms and children, for whom the efficacy and safety remain to be assessed.
Ginkgo finds a different approach to the research and development of anti-influenza programs. Two projects including influenza virus PA inhibitor and PB2 inhibitor are developed with a new blocking target of the RNA polymerase of influenza virus.
【Chronic HBV infection background】
Hepatitis B (HBV) is the most common and serious liver infections in the world. Persons infected with HBV are at increased risk of developing significant liver disease, including cirrhosis, liver failure and cancer. The American Hepatitis B Foundation estimates that about 300 million people worldwide are chronically infected, and each year about 1 million people die from HBV.
China is also facing the threat and according to an official conservative estimate, there are over 93 million people infected with chronic hepatitis B. Statistics from CDC shows that the reported number of HBV in China increased from 942,268 in 2016 to 1,001,952 in 2017. In addition, HBV infection accounts for 60% and 80% of patients with liver cirrhosis and hepatocellular carcinoma. Furthermore, since HBV is almost incurable after chronic infection, the potential of the anti-HBV drug market remains huge even with the preventive HBV vaccine.
Currently, there are 9 anti-HBV drugs have been approved worldwide, 2 of which are immunomodulators (interferons) and the rest are nucleotide replicase inhibitors.
The nucleotide analogs are generally well tolerated by inhibiting the activity of the polymerase required for HBV replication in hepatocytes, and are very effective in reducing HBV DNA levels to undetectable levels, but have little effect on hepatitis B surface antigen (HBsAg). Although the interferon drugs can mobilize the host's immune system against the virus, they have limited effects and weaker tolerance than nucleotide replicase inhibitors. The exploration that searching for new mechanism drugs that can effectively reduce the level of HBsAg, so as to achieve functional cure for more patients, has become one of the important directions of hepatitis B treatment.
In HBV program, Ginkgo aims to develop new drugs that suppress HBsAg levels. These drugs are designed to inhibit the generation of HBsAg and HBeAg by specifically degrading HBV mRNA.