Exploring Azvudine's Multiple Therapeutic Applications from Antiviral to Antitumor

Recently, the CBI2026 Biopharmaceutical Innovation Expo concluded in Suzhou. At the "Small Molecule Innovative Drug" forum, Dr. Li Pan, Senior Vice President of Genuine Biotech, shared the latest research advances on Azvudine in the treatment of incomplete immune reconstitution in human immunodeficiency virus (HIV) patients and in the antitumor field, focusing on its immunomodulatory mechanisms and clinical applications across multiple settings. As a domestically developed Class 1.1 innovative drug conditionally approved for marketing by the National Medical Products Administration (NMPA), Azvudine is expanding from an antiviral drug into a multi-indication platform.

Addressing the Clinical Challenge of Incomplete Immune Reconstitution in HIV Infection

Currently, highly active antiretroviral therapy (ART) is the standard treatment for HIV; it can sustainably suppress viral loads in patients to below the detection limit and substantially prolong survival. It is estimated that, despite sustained viral suppression, 10%–40% of HIV patients receiving ART experience incomplete CD4+ T-cell immune recovery, with CD4+ T-cell counts remaining persistently below normal levels. These patients are referred to as "immunological non-responders (INRs)".

According to Frost & Sullivan, the number of patients with HIV infection who are INRs worldwide exceeded 14.8 million in 2025. Compared with immunological responders, patients with HIV infection who are INRs face higher risks of opportunistic infections, malignant tumors, non-AIDS-defining events, and death. According to Frost & Sullivan, no therapy has been approved worldwide for the specific indication of treating INRs in patients with HIV infection.

Azvudine's unique advantage lies in its thymus-homing property. After entering the body, the drug can accumulate in the thymus, inhibit HIV replication, help restore CD4/CD8 immune equilibrium in the thymus, and thereby promote immune reconstitution at the source in INRs with HIV infection.

An investigator-initiated clinical trial showed that, after enrollment, patients with HIV infection who were INRs had Lamivudine in their existing ART regimen replaced with Azvudine 3 mg once daily, thereby forming an Azvudine-based triple antiretroviral treatment regimen. The results showed that Azvudine-based treatment regimens have the potential to effectively increase CD4+ T-cell counts, restore CD4/CD8 immune equilibrium, and promote immune reconstitution in INRs with HIV infection.

At present, Genuine Biotech has jointly applied with Peking Union Medical College Hospital, Chinese Academy of Medical Sciences to include the development of this indication as a National Science and Technology Major Project in 2025, and the application has been approved by the Ministry of Science and Technology of China.

Exploring the Dual Antitumor Mechanisms

In oncology, Azvudine exerts dual antitumor effects by inhibiting DNA synthesis in tumor cells and remodeling the immune microenvironment.

On the one hand, Azvudine is an efficient substrate for deoxycytidine kinase (dCK). After entering cells, it is converted into the active metabolite FNC-TP, which inhibits tumor cell proliferation by terminating DNA chain elongation and interfering with multiple enzymes involved in nucleic acid synthesis in cancer cells. Preclinical studies showed that Azvudine exhibited favorable inhibitory activity against solid tumor cells, including those of colorectal cancer, liver carcinoma, and non-small cell lung cancer.

On the other hand, Azvudine can act as an immunomodulatory agent, markedly reducing the infiltration of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. These cells are one of the key factors in forming an immunosuppressive barrier and causing the poor efficacy of immune checkpoint inhibitors. At the same time, Azvudine promotes the infiltration and proliferation of CD8⁺ T cells, CD4⁺ T cells, and NK cells. This immunomodulatory effect has been observed in preclinical models of solid tumors with high levels of MDSC infiltration, such as liver carcinoma, colorectal cancer, and non-small cell lung cancer, and helps convert "cold tumors" into "hot tumors".

In preclinical studies, 10x single-cell sequencing showed an increase in tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), memory T cells, and NK cells after Azvudine treatment, indicating increased antitumor effects and enhanced immune memory. Meanwhile, the numbers of immunosuppressive M2-like cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) decreased, indicating reduced immunosuppression.

Further in vitro validation with human primary cells demonstrated that Azvudine inhibited MDSC differentiation in a dose-dependent manner while promoting CD4⁺ and CD8⁺ T-cell proliferation and IFN-γ secretion.

Building the "Azvudine+" Platform Ecosystem

The immunomodulatory mechanism by which Azvudine converts "cold tumors" into "hot tumors" provides an important foundation for combination therapy.

In an animal model of microsatellite-stable (MSS) colorectal carcinoma, Azvudine monotherapy at 0.5 mg/kg achieved a tumor growth suppression rate of 57%, exceeding that observed with anti-PD-1 monotherapy. High-dose Azvudine in combination with a PD-1 inhibitor resulted in complete tumor regression in all animals. None of the cured mice developed tumors after being rechallenged with the same tumor cells.

Building on these findings, an investigator-initiated trial (IIT) provided additional exploratory clinical data in humans. Azvudine in combination with a PD-1 inhibitor and a VEGFR inhibitor has shown preliminary efficacy signals in the later-line treatment of microsatellite-stable (MSS) colorectal cancer. The combination therapy group demonstrated favorable safety and tolerability.

Based on thorough preliminary exploration, Genuine Biotech, in cooperation with Innovent Biologics, received IND approval from the NMPA in Feb. 2026 for the combination therapy of "Azvudine + Sintilimab" for the treatment of advanced solid tumors, marking its official entry into the clinical validation stage.

In another exploratory combination study, Azvudine in combination with a KRAS inhibitor also showed potential. KRAS inhibitors commonly encounter acquired resistance in clinical practice, involving multiple factors such as target mutations, bypass pathway activation, and adaptation to the microenvironment.

In the CT26-KRASG12C mutation model, the median survival time exceeded 66 days in the Azvudine plus KRASG12C inhibitor AMG510 combination therapy group, compared with 35 days in the AMG510 monotherapy group and 49 days in the PD-1 plus AMG510 group, suggesting that the combination of Azvudine and AMG510 may delay the development of resistance to AMG510.

Through further elucidation of its mechanism of action, expansion into new indications, and innovation in combination therapies, the clinical value of Azvudine continues to be explored and realized. In the future, Genuine Biotech will systematically build an "Azvudine+" platform innovation ecosystem through open collaboration, product innovation, patent protection, and global expansion, thereby providing more treatment options for unmet clinical needs.