ATG-010 (selinexor) is a first-in-class SINE compound targeting XPO1, a key nuclear export protein. It is the first and only SINE compound approved by the FDA. ATG-010 (selinexor) is approved for use in the treatment of two hematologic malignancies, namely multiple myeloma (MM) and DLBCL and is the only single-agent, orally-available therapy approved for the treatment of patients with R/R DLBCL. In addition to R/R MM and R/R DLBCL, promising research and data highlight the anti-cancer potential of ATG-010 (selinexor) for a wide range of cancer types, including both solid tumors and hematological malignancies.

ATG-010 (selinexor) functions by selectively binding to residue cysteine 528 (Cys528) in the cargo-binding groove of XPO1, inhibiting cargo binding and exporting by XPO1. Through inhibition of XPO1, ATG-010 (selinexor) blocks the nuclear export of tumor suppressors, growth regulators and anti-inflammatory proteins, leading to the accumulation of these proteins in the nucleus and enhancing anti-cancer activity in the cell.

We are in partnership with Karyopharm Therapeutics for clinical development, manufacturing and commercialization of selinexor in Greater China (mainland China, Hong Kong, Taiwan, Macau), Australia, New Zealand, South Korea, and the ASEAN countries. Antengene is conducting multiple clinical studies (including two registrational studies) of selinexor in China.

ATG-008 (onatasertib) is a second-generation, orally available mTOR kinase inhibitor being developed for the treatment of various advanced solid tumors and hematological malignancies. ATG-008 (onatasertib) blocks both mTORC1 and mTORC2, resulting in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation.

mTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTORC1 and mTORC2 are critical mediators of the PI3K-AKT pathway, which are frequently mutated in many cancers, leading to hyperactivation of mTOR signaling.

Inhibitors of the mTOR pathway, such as rapamycin and its analogs (i.e., rapalogs), predominantly inhibit mTORC1, and the efficacy of rapalogs may be partially restricted by their failure to prevent AKT activation through mTORC2, a functionally distinct mTOR complex, or by their limited inhibition of mTORC1-mediated phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which is a critical mediator of mTORC1’s effects on cell proliferation.

2017 Albert Lasker Basic Medical Research Award was granted to Michael N. Hall, who discovered the nutrient-activated TOR proteins and their central role in the metabolic control of cell growth.

We are in partnership with Celgene Corporation (now part of Bristol-Myers Squibb) for clinical development, manufacturing and commercialization of onatasertib in 14 countries and regions in Asia, including Greater China (mainland China, Hong Kong, Taiwan, Macau). We are currently conducting a total of three Phase I/II clinical trials on ATG-008 (onatasertib) to assess, among others, the safety and efficacy of ATG-008 (onatasertib) as a mono-or combination therapy for HBV+ HCC and various solid tumors carrying certain genetic alternation.

As a next-generation SINE compound that has shown initial signs of a broader therapeutic window, ATG-016 (eltanexor) could potentially enable higher dosing frequency and an extended period of exposure at higher levels. As a result, ATG-016 (eltanexor) may be used to target a wider range of indications. Given the encouraging efficacy and manageable safety profile demonstrated in the ongoing Phase I/II trial conducted by Karyopharm, we plan to conduct a Phase I/II clinical study for MDS as a fast-to-market strategy in China. Since there is no effective treatment option after hypomethylating agents, there are significant unmet medical needs for MDS patients.

We plan to further develop ATG-016 (eltanexor) for more prevalent indications in the APAC region such as KRAS-mutant solid tumors and virus infection related malignancies such as nasopharyngeal carcinoma.

We are in partnership with Karyopharm Therapeutics for clinical development, manufacturing and commercialization of eltanexor in Greater China (mainland China, Hong Kong, Taiwan, Macau), Australia, New Zealand, South Korea, and the ASEAN countries. We expect to initiate Phase 1/2 clinical trials in both hematological malignancies and solid tumors in 2021.

ATG-527 (verdinexor) is a SINE compound with a novel dual mechanism of action being developed for the treatment of viral infection. It inhibits the replication of viruses that utilize the XPO1 machinery for some aspect of their life cycle, while contributing to symptom relief via suppression of cytokine-mediated inflammatory responses. Inhibition of XPO1 does not rely on immune status for antiviral effects and may thus benefit immunocompromised patients.

Pre-clinical studies have demonstrated the broad spectrum anti-viral activity of ATG-527 (verdinexor), including against pandemic influenza strains and other viral classes, such as human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), hepatitis C virus (HCV) and EBV. Pre-clinical studies also showed promising data of ATG-527 (verdinexor) in the treatment of SLE where it significantly reduced total and germinal center B cells, plasmablasts and plasma cell production in lupus mouse model.

We are in partnership with Karyopharm Therapeutics for clinical development, manufacturing and commercialization of verdinexor in Greater China (mainland China, Hong Kong, Taiwan, Macau), Australia, New Zealand, South Korea, and the ASEAN countries. We plan to conduct a Phase I/II clinical trial for the treatment of CAEBV infection and SLE.

ATG-019 (KPT-9274) is a first-in-class, oral inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). The compound is currently in Phase I clinical trial for evaluation of its safety, tolerability and efficacy in patients with advanced solid malignancies or non-Hodgkin lymphoma.

PAK4 is a member of the PAK family kinases and a signaling protein regulating numerous fundamental cellular processes, including intracellular transport, cellular division, cell shape and motility, cell survival, immune defense and the development of cancer. PAK4 interacts with many key signaling molecules involved in cancer such as 13-catenin, CDC42, Raf-1, BAD and myosin light chain.

NAMPT is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor and hormone. It can be found in complex with PAK4. NAMPT is of interest as an oncology target because it catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide (NAD). NAD is a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, antioxidation and paradoxical generation of oxidative stress, gene expression, immunological functions, aging and cell death.

Co-inhibition of PAK4 and NAMPT may lead to synergistic antitumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Hematological and solid tumor cells that have become dependent on bothPAK4 and NAMPT pathways may be susceptible to single-agent cytotoxicity by ATG-019.

We are in partnership with Karyopharm Therapeutics for clinical development, manufacturing and commercialization of ATG-019 in Greater China (mainland China, Hong Kong, Taiwan, Macau), Australia, New Zealand, South Korea, and the ASEAN countries. We are conducting a Phase I clinical trial of ATG-019 in Taiwan and plan to conduct a combination study of ATG-019 and anti-PD-1 antibody to treat anti-PD-1 resistant patients.

ATG-017 (AZD0364) is a potent and selective small molecule extracellular signal- regulated kinases 1 and 2 (ERK1/2) inhibitor currently under clinical development for the treatment of various solid tumors, non-Hodgkin lymphoma, acute myeloid leukemia (AML) and MM.

ERK1/2 are related protein-serine/threonine kinases that function as terminal kinases in the RAS-MAPK signal transduction cascade. This cascade regulates a large variety of cellular processes, including proliferation. The RAS-MAPK pathway is dysregulated in more than 30% of human cancers with the most frequent alterations being observed in RAS or BRAF genes across multiple tumor types. An ERK inhibitor enables the targeting of both RAS and BRAF mutant diseases. In nonclinical pharmacology studies, ATG-017 has demonstrated potent inhibition of ERK1/2 enzyme activity and tumor growth in vitro and in vivo.

We entered into a partnership with AstraZeneca in 2019 and obtained exclusive global rights to develop, commercialize and manufacture ATG-017. We are conducting a Phase I clinical trial for the treatment of advanced solid tumors and hematological malignancies in Australia. We plan to explore the combination of ATG-017 with ATG-012, ATG-008 (onatasertib), MEK inhibitors and immune checkpoint modulators, including ATG-101.

ATG-101 is a novel, PD-L1/CD137 (4-1BB) bi-specific antibody being developed for the treatment of hematological malignancies and solid tumors. Pre-clinical research showed that the therapeutic efficacy of ATG-101 is superior to that of the combination of PD-L1 and CD-137 antibodies, which may be attributable to ATG-101’s ability to simultaneously bind tumor cells and T cells, leading to a potent tumor-localized T cell activation.

ATG-018 is a small molecule inhibitor targeting ataxia telangiectasia and Rad3 related (ATR) kinase being developed for the treatment of hematological malignancies and solid tumors.

ATG-037 is a highly potent, selective, orally-bioavailable small molecule inhibitor of CD37. It can reactivate antitumor immunity by inhibiting the highly immunosuppressive adenosine pathway.

CD73 is a rate-limiting enzyme that produces the highly immunosuppressive adenosine in the tumor microenvironment, thus leads to the immune escape of tumor cells. CD73 is expressed across a wide range of tumors and tumor infiltrating leukocytes, and often correlates with poor prognosis. Therefore, CD73 inhibition represents an effective approach in restoring antitumor immunity in caner patients. In addition, CD73 inhibition has great potential for combination with standard therapies or immune checkpoint inhibitors.

ATG-037 has demonstrated potent antitumor activity and a favorable safety profile in syngeneic animal models both as monotherapy and in combination with immune checkpoint inhibitors as well as chemotherapy, thus has great clinical potential either as a monotherapy or in combinations for the treatment of multiple tumor types.

ATG-022, an antibody drug conjugate targeting Claudin 18.2, is in the late pre-clinical research and GMP CMC stage.

ATG-012 is a KRAS G12C inhibitor against KRAS oncoprotein being developed for the treatment of solid tumors. Due to its unique MoA, it has the potential to be combined with many other therapies, including many of our own pipeline assets, such as ATG-017.

ATG-031 is a potential first-in-class anti-CD24 monoclonal antibody being developed for the treatment of hematologic malignancies and solid tumors. ATG-031 potently stimulates macrophage-mediated phagocytosis and induces the destruction of cancer cells by blocking the ‘Don’t eat me’ signals characterizing the growth of many cancers. In pre-clinical research, ATG-031 demonstrated single agent anti-tumor activity in animal models and showed synergy with chemotherapies, checkpoint inhibitors, and other therapeutic agents.

ATG-027 is a potential first-in-class bispecific antibody being developed for the treatment of hematologic malignancies and solid tumors. ATG-027 blocks the PD-1/PD-L1 interaction and the B7H3 interaction with its ligand to stimulate the activation of immune cells and mediates anti-tumor effect. ATG-027 also leads to the elimination of B7H3-positive tumor cells through ADCC/CDC effect. ATG-027 showed potent in vivo anti-tumor activity in mouse tumor models.