We have created a broad pipeline of drug candidates. 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. We are developing many of our drug candidates against multiple indications.
Updated as of September 13, 2018.
Notes: Proof-of-concept = Phase Ib/II study (the dashed lines delineate the start and end of small Phase Ib); combo = in combination with; brain mets = brain metastasis; VEGFR = vascular endothelial growth factor receptor; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor; NET = neuroendocrine tumors; ref = refractory, which means resistant to prior treatment; T790M= EGFR resistance mutation; EGFRm+ = EGFR activating mutations; EGFR+ = EGFR gene amplification; EGFR WT = EGFR wild-type; 5ASA = 5-aminosalicylic acids; chemo = chemotherapy; c-Met+ = c-Met gene amplification; c-Met O/E = c-Met over-expression; FGFR = Fibroblast Growth Factor Receptor; CSF1R = Colony Stimulating Factor-Receptor 1; NCI = U.S. National Cancer Institute; CCTG = Canadian Cancer Trial Group; Aus = Australia; Can =Canada; SK = South Korea; PRC = People’s Republic of China; Sp = Spain; UK = United Kingdom; US = United States; Global = >2 countries.
* The trial is focused on patients with MET Exon 14 mutation who have failed prior systemic therapy, or are unwilling or unable to receive chemotherapy, however the target patient population is intended to be all MET Exon 14 mutation patients.
Savolitinib is a potential global first-in-class inhibitor of the mesenchymal epithelial transition factor (c-MET) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. We designed savolitinib as a potent and highly selective oral inhibitor which through chemical structure modification addressed renal toxicity, the primary issue that halted development of several other selective c-MET inhibitors. In clinical studies to date, involving over 500 patients, savolitinib has shown promising signs of clinical efficacy and acceptable safety profile in patients with c-Met gene alterations in papillary renal cell carcinoma, non-small cell lung cancer, colorectal cancer, and gastric cancer.
We are currently testing savolitinib in partnership with AstraZeneca in multiple parallel studies, both as a monotherapy and in combination with other targeted therapies.
Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor receptor (VEGFR) and consequently we believe that it has the potential to be a global best-in-class VEGFR inhibitor for many types of 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 build-up of new blood vessels around a tumor, thereby contributing to the growth of tumors, and use in potential combinations with other agents such as chemotherapies, targeted therapies and immunotherapies. We believe these are points of meaningful differentiation versus other small molecule VEGFR inhibitors that have already been approved, and can potentially significantly expand the use and market potential of fruquintinib.
In partnership with Eli Lilly, we are currently studying fruquintinib in colorectal cancer, non-small cell lung cancer and gastric cancer in China. We have established a manufacturing (formulation) facility in Suzhou, China, which produces supplies of fruquintinib.
Surufatinib (HMPL-012 or sulfatinib)
Surufatinib is an oral drug candidate with a unique angio-immuno kinase profile which provides both anti-angiogenesis effect and, we believe, activates and effectively enhances the body’s immune system, specifically T-cells. Importantly, in 2016, we presented pre-clinical data that show surufatinib, in addition to inhibiting VEGFR and FGFR1, is a potent inhibitor of CSF-1R, a signaling pathway involved in blocking the activation of tumor-associated macrophages, which cloak cancer cells from attack from T-cells.
We are currently conducting multiple clinical trials of sulfatinib in disease areas such as pancreatic and non-pancreatic neuroendocrine tumors and biliary tract cancer, and retain all rights to sulfatinib worldwide. Surufatinib is the first oncology candidate that we have taken through proof-of-concept in China and expanded to a U.S. clinical study ourselves.
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.
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-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.
HMPL-453 is a potential first-in-class novel, highly selective and potent small molecule 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. To date, there are no approved therapies specifically targeting the FGFR signaling pathway. 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. We currently retain all rights to HMPL-453 worldwide.
In November 2012, we established Nutrition Science Partners, a joint venture with Nestle Health Science. The purpose of Nutrition Science Partners is to develop, manufacture and commercialize HMPL-004 for ulcerative colitis and Crohn’s disease and to identify, develop, manufacture and commercialize products in gastrointestinal indications.
We have worked with Nestle Health Science to prepare an IND application for HM004-6599, which was submitted in China in March 2017, and to prepare for a Phase I study of HM004-6599 in Australia in 2018. HM004-6599 is an enriched / purified re-formulation of HMPL-004, our drug candidate that reported positive Phase II results in ulcerative colitis in 2010 but then went on to prove futile in an interim analysis of the subsequent Phase III study in 2014. HM004-6599 has a higher level of biologically active components and improved manufacturing control, as compared to HMPL-004.