Realizing the complexity of the etiologies of liver diseases, Zhimeng has adopted a comprehensive approach to tackle the diseases by directly hitting the hepatitis B virus (HBV) with multiple pronged attacks, as well as restoring the host immune systems. Our mission is to deliver innovative, effective, safe and affordable therapies to bring a cure for patients suffering from CHB and improve the quality of life of patients with other liver diseases. Zhimeng also has 2 active programs for neurologic disorders that are ready for co-development with interested partners.
Brief descriptions of the projects
HBV capsid inhibitor (ZM-H1505R)
There are 250 million people worldwide who are chronic carriers of hepatitis B virus. In China, this patient population is about 90 million, of which about 30 million people have shown chronic hepatitis B (CHB) and need treatment. In China, more than 60% of hepatocellular carcinoma (HCC) cases is attributed to chronic HBV infection. Although current direct antiviral drugs (ETV, TDF, TAF etc.) can effectively control HBV replication and delay the progression of liver cirrhosis, they rarely cause a cure of CHB (loss of HBsAg is rarely achieved) and require infinite administration due to the frequent virus rebound upon the treatment cessation. Treatment with immune regulator pg-IFNα is only effective in 30% of patients with less than 10% achieving functional cure after one year of treatment. New therapies that either target the different steps of HBV life cycle or restore the host anti-HBV immunity are urgently needed. ZM-H1505R is a small molecule discovered at Zhimeng as a potent HBV capsid formation inhibitor. ZM-H1505R is currently being developed to significantly increase functional cure rate of CHB. ZM-H1505R has a novel chemical entity distinct from that of reported class I (heteroaryldihydropyrimidines, e.g., GLS4) and class II (phenylpropenamides or sulfamoylbenzamides, e.g., AT-130 and NVR3-778) HBV core protein allosteric modulators (CpAMs). More importantly, ZM-H1505R is active against virus variants that are resistant to both class I and class II CpAMs tested.
HBV RNA destabilizer
HBsAg has been indicated as the major viral factor to interfere with host immune response against the virus. HBsAg level in the serum is a hallmark for HBV replication activity. HBsAg is abundantly produced even the viral replication is under control by nucleoside drugs. In clinic practice, seroclearance of HBsAg is defined as “functional cure”. Shutting down the expression of HBsAg and restoring the immune response is our second prong for achieving a functional cure of HBV infection. Zhimeng is developing a series of small molecules that suppresses the expression of both HBsAg and HBeAg.
TLR8 agonist
Poor activation of innate immunity against HBV is another hallmark of chronic hepatitis B. Specific activation of TLR8 on myeloid DCs and monocytes leading primarily to the production of proinflammatory cytokines and chemokines, such as TNFα, IFNγ, IL-12 and IL-18. Controlled activation of TLR8 represents a novel therapeutic strategy for the treatment of infection of DNA viruses, such as HBV. As our third strategy to achieve function cure of CHB, we are currently developing a novel TLR8 agonist against HBV.
OX-40 agonist
Liver cancer (HCC) is the fifth most prevalent cancer worldwide and the second leading cause of death from cancer. Of all the 810,500 HCC deaths worldwide in 2015, 55% cases are reported from China. In China, the estimated incidence rate of HCC is 40.0 in males and 15.3 in females per 100,000. The five-year survival rate is between 10-18%. Primary liver cancer remains an important public health issue due to its extremely aggressive nature and poor survive rate. The leading causes of HCC are cirrhosis due to HBV, HCV and alcohol. Other causes are aflatoxin and non-alcoholic fatty liver disease. Current standard-of-care therapy for HCC is Sorafenib (Nexavar) which can only provide a marginal benefit of overall survival of 10.7 months vs 7.9 months of untreated patients. The other first-line targeted therapy Lenvatinib (Lenvima) and the second-line drug Regorafenib only provide an overall survival of < 15 months. Thus, new therapies are urgently needed to improve the quality of life and increase the life-span of HCC patients. OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed primarily on activated CD4+ and CD8+ T cells. Binding of OX40 ligand (OX40L) to the OX40 receptor triggers a co-stimulatory signal that increases the production of T cells and inflammatory cytokines within inflammatory lesions. Zhimeng is currently exploring the feasibility of activating OX40 for the treatment of CHB and HCC.
KCNQ2/3 K+ channel opener for epilepsy
Epilepsy is one of the most common neurologic diseases affecting approximately 50 million people worldwide (9 million are affected in China). There is a high unmet medical need in epilepsy: 30% of patients are considered refractory to current treatments, and another 30% are in need of better treatment options. Etiologically, epilepsy is caused by an unregulated overflow of K+ through neuron cells. KCNQ2/3 K+ channels are important regulators of cellular excitability in the brain. Retigabine (Potiga, Ezogabine) is the first neuronal KCNQ2/3 (K+) channel opener drug approved by FDA & EMA in 2011 for the treatment of patient refractory to other approved epilepsy drugs. Retigabine was withdrawn from market in 2017 due to blue skin discoloration and potential risk of vision loss. Zhimeng’s epilepsy compound CB03 is more potent for KCNQ2/3 than retigabine in cell-based assay and is highly efficacious in a broad range of epilepsy and pain animal models. Comparing to retigabine, CB03 has a much more favorable PK and safety profile to support a once daily dosing in human.