We are focused on two target therapeutic areas: oncology and immunological diseases.
We have created a broad pipeline of drug candidates. We have taken a chemistry-focused approach to develop highly selective small molecule tyrosine kinase inhibitors that are intended to have potentially global best-in-class efficacy and are deliberately engineered to improve drug exposure and reduce known class-related toxicities.
Some of our current drug candidates may have the potential to be global first-in-class therapies, while others may be sufficiently differentiated to potentially be global best-in-class, next generation therapies with a superior profile compared to existing approved drugs that act against the relevant kinase targets.
Updated as of March 4, 2021.
* Phase II registration-intent study subject to regulatory discussion; ** In planning; *** Investigator-initiated trials (IIT).
Note: MET = mesenchymal epithelial transition receptor, VEGFR = vascular endothelial growth factor receptor, TKI = tyrosine kinase inhibitor, EGFRm = epidermal growth factor receptor mutation, FGFR1 = fibroblast growth factor receptor 1, CSF-1R = colony stimulating factor-1 receptor, NET = neuroendocrine tumors, NEN = neuroendocrine neoplasms, ESCC = esophagealsquamous-cellcarcinomas, BTC = biliary tract cancer, SCLC = small cell lung cancer, GC = gastric cancer, TC = thyroid cancer, EMC = endometrial cancer, CRC = colorectal cancer, HCC = hepatocellular carcinoma, GI = gastrointestinal, Syk = spleen tyrosine kinase, PI3Kδ = Phosphatidylinositol-3-Kinase delta, NSCLC = non-small cell lung cancer, RCC = renal cell carcinoma, NHL = Non-Hodgkin’s Lymphoma, FL = follicular lymphoma, MZL = marginal zone lymphoma, MCL = mantle cell lymphoma, DLBCL = diffuse large B cell lymphoma, CLL/SLL = chronic lymphocytic leukemia/small lymphocytic lymphoma, HL = Hodgkin’s lymphoma, ITP = immune thrombocytopenic purpura, IHCC = Intrahepatic cholangiocarcinoma, IDH 1/2 = isocitrate dehydrogenase 1/2, ERK = extracellular-signal-regulated kinase, MAPK pathway = RAS-RAF-MEK-ERK signaling cascade.
Savolitinib is a potent and selective inhibitor of the mesenchymal epithelial transition factor, or MET, receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. We designed savolitinib through chemical structure modification to specifically address kidney toxicity, the primary issue that halted development of several other selective MET inhibitors. In clinical trials to date in over 1,000 patients globally, savolitinib has shown promising signs of clinical efficacy in patients with MET gene alterations in lung cancer, kidney cancer and gastric cancer with an acceptable safety profile.
We are currently testing savolitinib in global partnership with AstraZeneca, both as a monotherapy and in combination with immunotherapy and targeted therapy.
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.
Surufatinib has been approved in China for the treatment of non-pancreatic neuroendocrine tumors. In the United States, the FDA granted orphan drug designation to surufatinib for the treatment of pancreatic neuroendocrine tumors in November 2019 and granted Fast Track Designations for the treatment of both pancreatic neuroendocrine tumors and non-pancreatic neuroendocrine tumors in April 2020. In December 2020, we initiated a rolling NDA submission for surufatinib for the treatment of pancreatic and non-pancreatic neuroendocrine tumors. We own all rights to surufatinib globally.
Fruquintinib is a highly selective and potent oral inhibitor of three vascular endothelial growth factor receptors, known as VEGFR 1, 2 and 3. We believe that fruquintinib has the potential to become the global best-in-class selective small molecule VEGFR 1, 2 and 3 inhibitor for many types of solid tumors, and we are currently studying fruquintinib in colorectal cancer, gastric cancer and various other solid tumors. Based on pre-clinical and clinical data to date, fruquintinib’s kinase selectivity has been shown to reduce off-target toxicity. This allows for drug exposure that is able to fully inhibit VEGFR, a receptor tyrosine kinase which contributes to angiogenesis, the buildup of new blood vessels around a tumor, thereby contributing to the growth of tumors. Such selectivity also facilitates use in potential combinations with immunotherapy, targeted therapy and chemotherapy drugs. Fruquintinib has been approved for the treatment of third-line metastatic colorectal cancer in China.
HMPL-689 is a novel, highly selective and potent small molecule inhibitor targeting the isoform phosphoinositide 3’-kinase delta (PI3Kδ), a key component in the B-cell receptor signaling pathway. We have designed HMPL-689 with superior PI3Kδ isoform selectivity, in particular to not inhibit PI3Kɣ (gamma), to minimize the risk of serious infection caused by immune suppression. HMPL-689’s strong potency, particularly at the whole blood level, also allows for reduced daily doses to minimize compound related toxicity, such as the high level of liver toxicity observed with the first-generation PI3Kδ inhibitor. HMPL-689’s pharmacokinetic properties have been found to be favorable with good oral absorption, moderate tissue distribution and low clearance in pre-clinical pharmacokinetic studies. We also expect HMPL-689 will have low risk of drug accumulation and drug-to-drug interaction. Given this, we believe that HMPL-689 has the potential to be a global best-in-class PI3Kδ agent. We currently retain all rights to HMPL-689 worldwide.
We believe HMPL-523 is a potential global first/best-in-class oral inhibitor targeting spleen tyrosine kinase (Syk), a key protein involved in B-cell signaling. Modulation of the B-cell signaling system has been proven to significantly advance the treatment of certain chronic immune diseases, such as rheumatoid arthritis as well as hematological cancers. To date, only monoclonal antibody immune modulators, which seek to use the patient’s own immune system to treat the disease, have been approved. As an oral drug candidate, we believe HMPL-523 has important advantages over intravenous monoclonal antibody immune modulators in rheumatoid arthritis in that as small molecule compounds clear the system faster, thereby reducing the risk of infections from sustained suppression of the immune system.
Moreover, other drug development companies have tried to design small molecule Syk inhibitors for the treatment of chronic immune diseases, but designing an efficacious and safe Syk inhibitor has proven to be exceptionally difficult. No drug products targeting Syk have been approved to date due to severe off-target toxicity, such as hypertension, as a result of poor kinase selectivity. HMPL-523 is a potent and highly selective oral inhibitor specifically designed to overcome these off-target toxicity issues. We currently retain all rights to HMPL-523 worldwide.
HMPL-453 is a novel, potential best-in-class, highly selective and potent small molecule inhibitor that targets fibroblast growth factor receptor (FGFR) 1/2/3, a sub-family of receptor tyrosine kinases. Aberrant FGFR signaling has been found to be a driving force in tumor growth (through tissue growth and repair), promotion of angiogenesis and resistance to anti-tumor therapies. In pre-clinical studies, HMPL-453 demonstrated superior kinase selectivity and safety profile as well as strong anti-tumor potency, as compared to drug candidates in the same class. Abnormal FGFR gene alterations are believed to be the drivers of tumor cell proliferation in several solid tumor settings. We currently retain all rights to HMPL-453 worldwide.
HMPL-306 is a novel selective small molecule dual inhibitor of isocitrate dehydrogenase (“IDH”) 1 and 2 mutations. IDH1 and IDH2 mutations have been implicated as drivers of certain hematological malignancies, gliomas and solid tumors, particularly among acute myeloid leukemia patients. Cytoplasmic mutant IDH1 and mitochondrial mutant IDH2 have been known to switch to the other form when targeted by an inhibitor of IDH1 mutant alone or IDH2 mutant alone. By targeting both IDH1 and IDH2 mutations, HMPL-306 could potentially provide therapeutic benefits in cancer patients harboring either IDH mutation, and may address acquired resistance to IDH inhibition through isoform switching.
A significant portion of patients with non-small cell lung cancer go on to develop brain metastasis. Patients with brain metastasis suffer from poor prognosis. Epitinib is a potent and highly selective oral epidermal growth factor receptor (EGFR) inhibitor which has demonstrated brain penetration and efficacy in pre-clinical and now clinical studies. EGFR inhibitors have revolutionized the treatment of non-small cell lung cancer with EGFR activating mutations. However, approved EGFR inhibitors such as Iressa and Tarceva cannot penetrate the blood-brain barrier effectively, leaving the majority of patients with brain metastasis without an effective targeted therapy. We currently retain all rights to epitinib worldwide.
Like epitinib, theliatinib is a novel molecule epidermal growth factor receptor (EGFR) inhibitor under investigation for the treatment of solid tumors. Tumors with wild-type EGFR activation, for instance, through gene amplification or protein over-expression, are less sensitive to current EGFR tyrosine kinase inhibitors, Iressa and Tarceva, due to sub-optimal binding affinity. Theliatinib has been designed with strong affinity to the wild-type EGFR kinase and has been shown to be five to ten times more potent than Tarceva. Consequently, we believe that theliatinib could benefit patients with esophageal and head and neck cancer, tumor-types with a high incidence of wild-type EGFR activation. We currently retain all rights to theliatinib worldwide.