▶ Azvudine

Azvudine is the first dual-target nucleoside oral drug in the world to simultaneously target both reverse transcriptase and viral infectivity factor for the treatment of HIV infection. It was conditionally approved by the NMPA in Jul. 2021 for the treatment of HIV-1 infected patients who are 18 or older with high viral load (the number of HIV-1 infected patients accounts for over 90% of all HIV-infected patients globally). Azvudine has three significant advantages. 1) Higher potency: The clinical efficacy of 3 mg Azvudine is comparable to that of 300 mg lamivudine. 2) Lower risk of drug resistance: It can be used in patients resistant to current NRTIs (including lamivudine). The dual-target mechanism of action of Azvudine makes it less likely to result in drug-resistance. 3) Potential to be an oral long-acting treatment: As shown in a human pharmacokinetic study, the active form of Azvudine can still be detected in peripheral blood mononuclear cells (PBMC) 120 hours after drug administration. Azvudine has been listed as one of the National Science and Technology Major Projects (Major New Drug Innovation), and it was included in the Chinese guidelines for the diagnosis and treatment of HIV/AIDS, solidifying its position as a recommended drug for HIV treatment.

Azvudine could be administered in combination with antiretroviral drugs of different mechanisms and functions as the backbone medication in various two-drug or three-drug ART regimens. In the Phase II clinical trial, Azvudine achieved clinical efficacy comparable to that of another popular NRTI at a much lower dosage level, and it is less likely to result in drug-resistance compared to single-target NRTIs given its dual-target mechanism. Moreover, Azvudine has demonstrated the potential to become part of an oral long-acting treatment for HIV infection due to its long-acting feature. To further exploit the strength of Azvudine, we plan to develop composite tablets for the treatment of HIV infection with Azvudine being the main ingredient and combined with other drugs for improved efficacy.

▶ CL-197 

CL-197 is a novel oral HIV drug candidate under development with potential long-acting effect. The IND application for CL-197 submitted in China was approved in Oct. 2022. As demonstrated in preclinical trials, CL-197 is able to effectively suppress HIV replication. CL-197 will be administered orally and has the potential of being administered only once per week. Such relatively convenient drug regimen may also improve medication adherence and thus improve clinical outcomes. Both Azvudine and CL-197 have demonstrated long-acting features in preclinical trials, and the combination of them has the potential to become the world's first all-oral long-acting regimen for the innovative treatment of HIV.

▶ Azvudine/DTG composite tablet

Azvudine has the potential to be developed into various HIV composite tablets in combination with other antiretroviral medications of different mechanisms and functions given its dual-target mechanism of action. We are developing an Azvudine/DTG composite tablet for the treatment of HIV infection. With Azvudine being the main active ingredient, we plan to combine it with dolutegravir (DTG), a commercialized antiretroviral drug, for potentially improved efficacy. Each of these drugs attacks HIV through different targets and, together, they help prevent the drug resistance that occurs over time with single-drug medication. We have commenced a drug-drug interaction clinical study to evaluate interactions between Azvudine and DTG for the composite tablet.

▶ All-oral long-acting composite tablet

We also plan to develop an all-oral long-acting composite tablet based on the potential combined long-acting effect and combined mechanisms of action of Azvudine and CL-197 for the prevention and treatment of HIV infection. The composite tablet has the potential to be administered weekly and improves medication adherence. The IND application for CL-197 submitted in China was approved in Oct. 2022.

▶ Azvudine

Azvudine is a broad-spectrum RNA virus inhibitor. As a synthetic nucleoside analogue of the viral RNA-dependent RNA polymerase (RdRp), it is metabolized intracellularly into an active antiviral metabolite 5'-triphosphate (azvudine triphosphate) that specifically targets the SARS-CoV-2 RdRp. It is incorporated into the viral RNA chain during RNA synthesis of SARS-CoV-2 virus, thereby terminating the replication of SARS-CoV-2 virus and exerting therapeutic effects against SARS-CoV-2 infection.

Azvudine tablets is the first oral small-molecule antiviral drug for the treatment of COVID-19 developed in China with fully independent intellectual property. On Jul. 25, 2022, it was approved by NMPA for the treatment of common COVID-19 in adults. On Aug. 9, 2022, the General Office of the NationaAzvudine is the first oral small-molecule drug independently developed in China for the treatment of COVID-19 and was conditionally approved by the NMPA on Jul. 25, 2022. On Aug. 9, 2022, the General Office of the National Health Commission and the Office of National Administration of Traditional Chinese Medicine included Azvudine tablets in the Diagnosis and Treatment Guideline for COVID-19 (9th Edition). On Dec. 7, 2022, Azvudine was included in the latest version of Clinical Pharmacy Guideline for Antiviral Treatment of COVID-19 published by Guangdong Pharmaceutical Association. On Dec. 17, 2022, Henan Pharmaceutical Association published the Expert Consensus on the Use of Azvudine for the Treatment of COVID-19. On Jan. 6, 2023, Azvudine was included in the Diagnosis and Treatment Guideline for COVID-19 (10th Edition). In Jan. 2023, 34 experts in infection, respiration, critical care, and pharmacy were convened by the National Center for Infectious Diseases to publish the Expert Consensus on Antiviral Treatment for COVID Patients, and Azvudine tablets was highly recognized. On Jan. 18, 2023, Azvudine tablets was officially included in the National Reimbursement Drug List. In Feb. 2023, Azvudine was approved for marketing by the Ministry of Health of the Russian Federation (registration certificate no.: ЛП-008750) and officially became a drug for the treatment of COVID-19 in Russia.

▶ Dosimertinib

The company's investigational drug candidate Dosimertinib is a highly potent, selective and orally administered epidermal growth factor receptor (EGFR)-targeting drug for the treatment of advanced EGFR mutation-positive non-small cell lung cancer (NSCLC), one of the most prevalent types of lung cancer in China. Dosimertinib showed dose-dependent inhibitory activities toward patient-derived xenocraft models of EGFR mutation-positive NSCLC cell lines BaF3, HCC827 and NCI-H1975 in preclinical studies. Among them, HCC827 was the most sensitive to dosimertinib. At the same dosage level, dosimertinib exhibited dose-dependent inhibitory activities comparable to that of osimertinib on the three selected cancer cell lines. Animal studies have shown that dosimertinib reduced the level of toxic metabolites (mainly AZ5104) by up to 80% compared to osimertinib. We have received NMPA approval for a Phase I/II clinical trial to evaluate the safety, tolerance, pharmacokinetic characteristics, and preliminary efficacy of dosimertinib for the treatment of advanced EGFR mutation-positive locally advanced or metastatic NSCLC patients. Currently, we have commenced the patient recruitment process and plan to complete the Phase I/II trial in 2026.

▶ Azvudine 

Considering the potential anti-tumor activity of Azvudine as a nucleoside-based drug, which has been shown to interfere with the synthesis of nucleic acids in cancer cells, we are also developing Azvudine for the treatment of certain types of blood cancer. Preclinical in vitro studies results demonstrated that Azvudine has potent activity against multiple myeloma, lymphoma, and acute leukemia cancer cell lines. We have completed the preclinical studies.

▶ ZS-1001

ZS-1001 is an inhibitor of CD73. CD73 facilitates the immune evasion of tumor cells, and drugs targeting CD73 can arrest tumor progression and metastasis, and have synergistic effects in combination with immunotherapeutic drugs for cancers.

▶ ZS-1002

ZS-1002 is an inhibitor of ENPP1. By inhibiting ENPP1, it selectively upregulates cGAMP, a signaling molecule that stimulates immune response, within the tumor, thereby increasing the efficacy of existing IO therapies.

▶ ZS-1003

ZS-1003 is an anti-cancer drug targeting TOPO1. TOPO1 participates in the overwinding or underwinding of DNA, and is particularly vulnerable to TOPO1 inhibitors during the cleavage reaction, meaning that they can be trapped by anti-cancer drugs as they cleave DNA in cancer cells.

▶ MTB-1806

MTB-1806 is a small-molecule drug candidate indicated for AIS. MTB-1806 has demonstrated its efficacy in pharmacodynamic studies, where it effectively reduced the infarction volume and the brain swelling volume as observed in middle cerebral artery occlusion rat models and improved the neurobehavioral score. Additionally, under a lower drug dosing regimen, MTB-1806 was still able to reduce cerebral edema and neurological deficits in rats with global ischemia-reperfusion injury, demonstrating efficacy comparable to NBP, an NMPA-approved drug, under a higher dosing regimen.