Apatinib
The First Small-Molecule Targeted Therapy for Late-Stage Gastric Cancer
Vascular endothelial growth factor receptors (VEGFR) are a family of receptor tyrosine kinases, which play an important role in both vasculogenesis and angiogenesis. Among all subtypes, VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. A series of VEGFR inhibitors were approved for oncology treatment, and more molecules are under development.
Apatinib is a selective VEGFR-2 inhibitor which also mildly inhibits c-Kit and c-Src tyrosine kinases. It is the first approved small-molecule targeted therapy for late-stage gastric cancer in the world, with good efficacy and safety profiles demonstrated in both pre- and post-marketing studies.
Apatinib is marketed in China and is involved in a number of clinical studies for combination therapy.
Pyrotinib
A Novel, Irreversible EGFR/HER2/HER4 TKI for Breast Cancer
Pyrotinib is a novel, irreversible, small-molecule inhibitor of EGFR/HER2/HER4. It received the first conditional approval in China history in August 2018 for the treatment of relapsed or metastatic HER2-positive breast cancer.
In the registration clinical trial in China, pyrotinib + capecitabine showed superior PFS and ORR than lapatinib + capecitabine in metastatic HER2-positive breast cancer (ORR: 78.5% vs. 57.1%; PFS: 18.1 months vs. 7.0 months). Moreover, preliminary results of another phase II study in HER2 mutant advanced NSCLC patients are promising.
Five more clinical trials in HER2-positive breast cancer and HER2 mutant NSCLC patients are ongoing in China and the U.S.
Mecapegfilgrastim
A Novel Long-Acting PEG-rhG-CSF
Neutropenia is a common adverse effect for as many as one in three patients receiving chemotherapy. Granulocyte-colony stimulating factor (G-CSF) stimulates the production of granulocytes, including neutrophils. In oncology and hematology, a recombinant form of G-CSF is used to accelerate recovery and reduce mortality from neutropenia associated with chemotherapy, allowing higher adherence to the prescribed chemotherapy regimens.
Mecapegfilgrastim is a novel PEGylated human recombinant G-CSF that enables once per chemotherapy cycle injection, rather than daily injection. A total of five completed/ongoing clinical trials (including one Ia trial in healthy volunteers) among NSCLC and breast cancer patients have fully validated mecapegfilgrastim’s superior ability to reduce neutropenia.
Mecapegfilgrastim received marketing approval in China in July 2018.
SHR3680
A Novel Small-Molecule Antagonist of Androgen Receptor for Prostate Cancer
Androgen receptor (AR) is a ligand-dependent transcription factor. AR overexpression is identified as a frequent driver of castration-resistant prostate cancer (CRPC). AR plays a critical role in cell growth in CRPC despite low serum androgen levels.
SHR3680 is a small-molecule full AR antagonist for prostate cancer without agonistic activity.
One phase I/II trial was completed in China. Currently, there are 3 phase I or I/II trials ongoing in China and Australia. A phase III trial targeting mHSPC is also ongoing in China.
SHR3162:
A Novel PARP Inhibitor in Clinical Stage
Poly ADP ribose polymerase (PARP) is an enzyme that detects and initiates an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks. In BRCA1/2 mutated cancer cells, where the double-strand DNA break repairing function was damaged, the inhibition of PARP induces death of cancer cells but not normal cells.
SHR3162 is a clinical-stage PARP inhibitor being developed to address ovarian cancer, breast cancer, gastric cancer, and other solid tumors.
One phase I clinical trial was completed in patients with advanced tumors. SHR3162 is also being developed in combination with other anti-tumor drugs.
SHR9549:
A Novel 2nd-Generation SERD with Potent Anti-Tumor Activity
Breast cancer is the most common type of cancer in women both in the developed and developing world. About 80% breast cancers are estrogen receptors (ER)-positive. These cancers depend on the ER signaling for proliferation and survival.
Selective estrogen receptor degraders or down-regulators (SERDs) bind to ER and cause ER to be degraded. As a result, cell proliferation is decreased. SERDs are used to treat ER-sensitive breast cancer, along with older classes of drugs like SERMs and aromatase inhibitors.
SHR9549 is a 2nd generation oral SERD which showed satisfying efficacy and safety profiles in preclinical studies.
SHR9549 is currently in phase I clinical development.
SHR2554
A Novel Small-Molecule Inhibitor of EZH2
Enhancer of zeste homologue 2 (EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2), which silences tumor suppressor genes in cancer cells. Selective inhibition of histone methyltransferase EZH2 downregulates the methylation of H3K27, reducing tumor cell proliferation.
SHR-2554 inhibits the wild-type and mutated histone methyltransferase EZH2, preventing the methylation of H3K27. As a result, it alters gene expression patterns associated with cancer pathways and decreases tumor cell proliferation in EZH2 mutated cancer cells.
SHR-2554 is under phase I clinical trials in China and Australia for the treatment of relapsed or refractory mature lymphoid neoplasms and metastatic castration resistant prostate cancer.
SHR7390: A Novel 2nd-Generation MEK Inhibitor to Address Solid Tumors
MEK is a key component of the RAS-RAF-MAPK signaling pathway. Deregulation of this pathway occurs in more than 30% of human cancers. MEK is a therapeutic target in a number of cancers such as melanoma, non-small cell lung cancer, and colorectal cancer..
SHR7390 is a clinical-stage, 2nd-generation MEK1/2 inhibitor, which effectively abolishes the paradoxical activation of the MAPK pathway by BRAF inhibitor.
Two clinical phase I studies to treat solid tumors are ongoing in China, featuring both monotherapy and combination with a PD-1 antibody.
SHR1459:
A Novel BTK Inhibitor
Bruton's tyrosine kinase (BTK) is an essential component of the BCR signaling pathway. Inhibition of BTK has been demonstrated to be an effective treatment for B-cell malignancies and autoimmune diseases.
SHR1459 is a novel, orally available, and covalently-bound BTK inhibitor that exhibits unique pharmacologic properties compared with other BTK inhibitors.
SHR1459 is currently in phase I clinical development in both China and Australia.
On Jan 8th 2018, TG Therapeutics licensed from Hengrui worldwide rights, excluding Asia but including Japan, for the development and commercialization of SHR1459 for hematological indications.
SHR-1309
A Monoclonal Antibody against HER2 (Trastuzumab Biosimilar)
Human epidermal growth factor receptor 2 (HER2) protein is a surface molecule essential for tumor growth. The overexpression of HER2 was found in multiple types of solid tumors, including breast cancer, bladder cancer, and colorectal cancer etc.
SHR-1309 is a monoclonal antibody targeting HER2, a biosimilar to trastuzumab that inhibits HER2-positive tumor growth. SHR-1309 is currently in phase I clinical development in China.
SHR-A1201
Trastuzumab-ADC
Human epidermal growth factor receptor 2 (HER2) protein is overexpressed in approximately 20% breast cancers with an aggressive phenotype. Trastuzumab is the first approved, humanized monoclonal antibody targeting HER2 to treat HER2-positive breast cancer. Trastuzumab-emtansine (T-DM1), an antibody-drug-conjugate (ADC) developed later, has shown better clinical efficacy.
SHR-A1201 is an antibody-drug-conjugate that covalently links trastuzumab and a potent toxin. SHR-A1201 is currently evaluated in a phase I clinical trial.
Camrelizumab
A Novel Anti-PD-1 Antibody
Programmed cell death protein (PD-1) is an immune checkpoint that guards against autoimmunity and prevents the immune system from killing cancer cells. Anti-PD-1 antibody blocks the interaction between PD-1 and PD-L1, activating the immune system to kill cancer cells. In recent years, PD-1/PD-L1 antibodies have become the backbone of immune oncology therapies.
Camrelizumab is an anti-PD-1 antibody pending NMPA (i.e. CFDA) marketing approval. In completed clinical trials, camrelizumab showed competitive efficacy in classic Hodgkin’s lymphoma and nasopharyngeal carcinoma, with a good safety profile.
2 NDA-enabling trials were completed and 20 other phase I/II/III trials are ongoing.
Famitinib
A Novel TKI for Cancer and Idiopathic Pulmonary Fibrosis
Famitinib is a novel, multi-targeted receptor tyrosine kinase inhibitor with potential antineoplastic activity that primarily targets VEGFR2, c-Kit, and PDGFR.
Three phase I or II trials were completed in China on solid tumors. Phase III clinical trials in colorectal cancer as well as other Phase I/II trials are ongoing (including combination use with camrelizumab, an anti-PD-1 product soon to be launched in China). Famitinib is also under development for the treatment of idiopathic pulmonary fibrosis.
SHR6390
A Novel CDK4/6 Inhibitor
Cyclin-dependent kinases 4 and 6 (CDK4/6) are key components of cell cycle progression and are dysregulated in cancers. Inhibition of CDK4/6 induces G1 phase cell cycle arrest, thus retards tumor growth.
SHR6390 is a novel CDK4/6 inhibitor. It shows a good safety profile in human. SHR6390 is currently assessed in a phase II clinical trial.
SHR-1316
A Novel Anti-PD-L1 Antibody
In many types of human tumors, programmed cell death ligand 1 (PD-L1) is highly expressed. Such high expression is often associated with poor prognosis.
SHR-1316 is a humanized IgG4 monoclonal antibody that binds specifically to human PD-L1, thereby interrupting the interaction of PD-L1 with PD-1 and B7-1 receptors. SHR-1316 is being developed for the treatment of solid tumors and hematologic malignancies. It demonstrated competitive anti-tumor efficacy and safety profiles in pre-clinical studies, as well as a desirable CMC profile.
SHR-1316 is currently being evaluated in phase I clinical trials in both China and Australia.
SHR-1501
Complex of IL-15 and IL-15 Rα/Fc Fusion Protein
IL-15 induces proliferation and activation of natural killer cells and CD8+ T cells to activate both innate and adaptive immunity to maximize patients’ immune response against tumor. Meanwhile, IL-15 neither stimulates Treg proliferation, nor promotes activation-induced T-cell death.
SHR-1501 is an IL-15 super-agonist to boost the immune system. SHR-1501 features extended half-life via a unique Fc fusion design and improved stability by cross linking IL-15 with IL-15Rα Sushi domain through a disulfide bond.
Two clinical trials in combination with a PD-L1 antibody (SHR-1316) are in preparation in China and the U.S.
SHR-1603
An Anti-CD47 mAb Targeting the CD47-SIRPα Pathway
CD47 is a transmembrane glycoprotein that inhibits the phagocytosis of macrophages through a signaling cascade. Through this pathway, tumor cells release signals to macrophages to escape from macrophage-mediated immune surveillance.
SHR-1603 inhibits the CD47-SIRPα pathway to block the signaling from tumor cells to macrophages, enhancing the phagocytosis of macrophages to tumor cells.
SHR-1603 is under phase I development in China for the treatment of advanced solid tumors and lymphoma. Combination therapies with PD-1 and PD-L1 antibodies are in preparation.
SHR-1701
A Bi-Functional Fusion Protein Targeting PD-L1 and TGF-β
Secretion of TGF-β and upregulation of immune checkpoint PD-L1 are two main contributors to immune evasion and tumor progression.
SHR-1701 is an investigational bi-functional fusion protein composed of a mAb against PD-L1 fused to the extracellular domain of human TGF-β receptor II, designed to simultaneously block the two immunosuppressive signaling pathways commonly used by cancer cells.
SHR-1701 is under phase I clinical trial for the treatment of metastatic or locally advanced solid tumors in China.
SHR-1702
A Novel Anti-TIM-3 Antibody
T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) functions as a T-cell inhibitory receptor to limit the duration and magnitude of Th1 and Tc1 T-cell response. The blockage of TIM-3 knocks out the immune suppression in tumor tissues, restoring function of disabled CD8+ T cells. It also showed a potential synergy with anti-PD-1 antibody.
SHR-1702 is a novel anti-TIM-3 antibody under development for the treatment of solid tumors and hematological malignancies. One phase I clinical trial is currently in preparation.
SHR-A1403 (HTI-1066)
A Novel Therapeutic Strategy with c-Met ADC
SHR-A1403 is an anti-c-Met monoclonal antibody conjugated to a microtubule inhibitor, targeting amplified MET and c-Met-overexpressing tumors, irrespective of MET pathway dependence.
SHR-A1403 is under phase I trial development in China and the U.S. for the treatment of NSCLC, colorectal cancer, and gastric cancer.