Shanghai: Friday, April 4, 2014: HMP today announces that data from certain preclinical and clinical studies will be presented at the 105th Annual Meeting of the American Association for Cancer Research (“AACR”) to be held in San Diego, California, USA from 5 to 9 April 2014. These presentations will include additional data on volitinib (HMPL-504/AZD6094) and epitinib (HMPL-813), two novel and highly selective small molecule drugs discovered by HMP. Presentations on volitinib were prepared jointly with HMP’s collaboration partner AstraZeneca AB (publ) (“AstraZeneca”).
AACR is the world’s first and largest professional organisation dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees.
HMP will have one oral presentation encompassing the substantial research and early clinical evaluation of volitinib, as well as two poster presentations focused specifically on c-Met models in preclinical studies of volitinib, and on epidermal growth factor receptor (“EGFR”) inhibition in esophagus cancer.
|1st Session:||New Drugs on the Horizon|
|Date:||Sunday, 6 April 2014|
|Presentation Title:||Discovery, preclinical and early clinical evaluation of volitinib: A potent and selective c-Met kinase inhibitor|
|2nd Session:||Kinase Inhibitors|
|Date:||Monday, 7 April 2014|
|Presentation Title:||A study on EGFR gene amplification and protein expression in Chinese esophagus cancer patients and anti-tumor activity of an EGFR inhibitor epitinib in patient derived esophagus cancer models|
|3rd Session:||Preclinical Studies in Model Organisms|
|Date:||Tuesday, 8 April 2014|
|Presentation Title:||Targeting MET in preclinical models to support the clinical development of volitinib in non-small cell lung cancer (“NSCLC”)|
Presentations will be made available at http://www.hmplglobal.com/en/publications/. Further information about the 2014 AACR Annual Meeting and the abstracts are available in Notes to Editors and at http://www.aacr.org.
AACR 2014 Presentation Abstracts
Discovery, preclinical and early clinical evaluation of volitinib: A potent and selective c-Met kinase inhibitor
Aberrant activation of c-Met signalling pathway has been identified to drive tumor growth/invasion and be involved in drug resistance. Targeting c-Met pathway represents a compelling opportunity to new anti-cancer therapies. Volitinib (HMPL-504/AZD6094) is a potent small molecule c-Met kinase inhibitor with IC50s in low nanomolar range at enzyme and cell levels. It was found to be highly selective in a screen against a broad panel of kinases. Volitinib has favourable pharmacokinetic properties and demonstrated strong anti-tumor activity in various human xenograft models harbouring c-Met gene amplification and/or protein over-expression. Strong pharmacokinetic/pharmacodynamic and target/tumor growth inhibition relationship was observed in the anti-tumor efficacy studies. In preclinical safety evaluation, volitinib was found to have favourable safety profile with large predicted safety margins. Volitinib is currently in Phase I clinical development. Detailed results on chemistry structure-activity relationship, including the chemical structure of volitinib and the strategy to address renal toxicity seen with other c-Met inhibitors, in vitro and in vivo evaluation including pharmacokinetic/pharmacodynamic correlation, pharmacokinetic and drug metabolism characterisation, and non-clinical safety evaluation will be presented.
A study on EGFR gene amplification and protein expression in Chinese esophagus cancer patients and anti-tumor effect of an EGFR inhibitor in patient-derived esophagus cancer models
Esophagus cancer is the fifth most common malignancy and the fourth leading cause of cancer mortality in China. According to Chinese cancer registry annual report in 2012, esophagus cancer accounts for nearly 1 in 10 of all cancer deaths. Despite the fact that much progress has been made in diagnosis and systemic chemotherapy regimens, the overall prognosis of esophagus cancer is disappointing. The 5-year survival rate, all stages included, is around 15-25%. There remains a significant unmet medical need for esophagus cancer treatment.
EGFR expression was reported in 30-90% esophagus cancers and over-expression of EGFR was found to be associated with poorer survival. Unlike colon cancer, K-ras mutation was less frequently found in esophagus cancer (5-10%), suggesting EGFR pathway blockade might bring therapeutic benefit to those patients with EGFR activation or over-expression. In this study, as of November 2013, 35 surgical esophagus tumor samples were collected from a local hospital in Shanghai. 31 of the 35 samples were identified as squamous cell carcinoma. EGFR gene amplification, protein expression and K-ras mutation were studied. In addition, 9 patient derived esophagus cancer xenograft models (“PDX”) were developed and anti-tumor effect of a novel and highly potent EGFR inhibitor was evaluated in 6 PDX models.
Positive EGFR protein expression was found in 66% (23/35) of esophagus cancer samples. EGFR gene amplifications were observed in 9% patients (3/35). In 9 established PDX models, 7 of them showed EGFR expression and 2 with EGFR gene amplification. No K-ras mutation was observed in the 9 models. A novel and highly potent EGFR inhibitor (“EGFRi”), developed by HMP and currently being evaluated in phase I clinical trials in China, demonstrated potent anti-tumor activity in several PDX models with tumor growth inhibition in a range of 70% to >100%. One PDX model with EGFR gene amplification and over-expression exhibited the highest sensitivity to EGFRi with remarkable tumor regression. EGFR signalling transduction was evaluated and the EGFRi inhibited phosphorylation of EGFR and downstream signalling molecules AKT and ERK.
In conclusion, EGFR expression and/or gene amplification was frequently found in Chinese esophagus cancer. EGFR inhibition resulted in potent anti-tumor effect in multiple patient derived esophagus cancer models carrying EGFR amplifications or high expression, suggesting the potential benefit that anti-EGFR agents might bring to esophagus cancer patients with abnormal EGFR activation.
Targeting MET in preclinical models to support the clinical development of volitinib in NSCLC
MET is a transmembrane tyrosine kinase receptor that is deregulated (gene amplification, mutation and over-expression) across multiple cancer types. Signalling through MET is normally activated through interactions with its specific ligand, hepatocyte growth factor (“HGF”). Aberrant MET/HGF activation can stimulate tumor growth, promote angiogenesis, induce metastasis and may contribute to resistance mechanisms in several tumor types. Several non-selective MET inhibitors have entered clinical development; results have been mixed based on potency, selectivity, and/or patient selection. Volitinib is a potent (IC50 4 nM) and selective (>650 fold selectivity over 265 kinases), small molecule inhibitor of MET. Recent evaluation of volitinib across a panel of cancer cell lines demonstrated selectivity for MET-driven disease, with MET amplified cell lines being most sensitive (IC50s of 1nM) and also suggesting limited off target activity. Volitinib resistant cell lines with MET amplification were identified and used to better understand the relationship of concurrent mutations with response. In addition to cancer cell line selectivity, we are analysing preclinical models of NSCLC that are representative of key patient segments, namely MET amplification and over-expression. In newly diagnosed NSCLC adenocarcinomas, focal MET amplification events represent ~3% of the population while over-expression of MET (without gene amplification) is observed in the majority of patients. In preclinical models, focal Met amplification in EBC-1 and NCI-H1993 caused significant tumor growth inhibition, confirming sensitivity to volitinib. Given the prevalence of over-expression in NSCLC, however, we sought to build a platform of evidence for the therapeutic use of volitinib in preclinical models lacking amplification of the MET gene. Using a patient-derived xenograft model (PDX) of EGFR wild-type (“WT”), KRAS WT and metastatic NSCLC disease (HLXF-036LN), we demonstrate that volitinib induces tumor regression as monotherapy and has added therapeutic benefit when used in combination with taxotere. In addition, we show robust efficacy effects for additional preclinical models, LG0567, LG0645 and Calu-3, for either volitinib alone or in combination with taxotere. In parallel pharmacodynamic studies, we demonstrate that volitinib inhibits p-MET and downstream signalling in each model. Together, using an integrated platform of molecular characterization and MET FISH and IHC scores, corresponding anti-tumor responses to volitinib are being evaluated for several patient segments. We are using these studies to inform the design of patient selection criteria for upcoming clinical trials in NSCLC.
About the c-Met signal pathway
The c-Met (also known as HGFR) signalling pathway has specific roles particularly in normal mammalian growth and development. However, this key pathway has been shown to function abnormally in a range of different cancers. Aberrant pathway activation can lead to uncontrolled tumor cell growth, invasion and survival. There are four different mechanisms of c-Met pathway activation: c-Met gene amplification, HGF/c-Met over-expression, mutation, and cross talk with other receptors. C-Met gene amplification is more prevalent in stomach, head & neck and colon cancers; whereas c-Met over-expression is found in many solid tumors, including lung, stomach, head & neck, colon, and esophagus cancers. Moreover, many of these tumors are of relevance to the Asian population, such as lung, stomach, and esophagus cancers (with EGFR mutations).
The estimated incidence of lung cancer worldwide was over 1.6 million in 2008, with over 520,000 cases in China. Lung cancer is the most common cancer both worldwide and in China.
Volitinib (HMPL-504/AZD6094) is a potent and highly selective small molecule inhibitor of the c-Met receptor with opportunities in lung, gastric, renal and other cancers. It has been demonstrated to inhibit the growth of tumors in a series of preclinical disease models, especially for those tumors with aberrant c-Met signalling such as gene amplification or c-Met over-expression. In addition, these biomarkers provide the potential to explore patient selection strategies in later stage clinical trials. In December 2011, HMP signed a global licensing deal with AstraZeneca on volitinib and then followed up with the start of Phase I study in Australia in February 2012. In June 2013 HMP initiated a Phase I study of volitinib in Asian patients in China.
To date, volitinib has demonstrated good safety and tolerability and favourable pharmacokinetic properties in late stage cancer patients. It has shown encouraging anti-tumor activity in several tumor-types, in particular in relation to papillary renal cell carcinoma (“PRCC”), a form of kidney cancer for which there is no specifically approved therapy on the global market. PRCC represents about 10-15% of all new cases of kidney cancer. Mutation leading to aberrant activation of the c-Met signalling pathway has been well documented in PRCC and effective inhibition of c-Met has been considered a potential treatment pathway for PRCC.
The results from the Phase I studies are planned to be released at the 50th annual meeting of the American Society of Clinical Oncology which will be held from 30 May to 3 June 2014 in Chicago, Illinois, USA. Phase II proof-of-concept studies on several tumor-types with c-Met amplification, mutation, or over-expression are being planned to start in 2014.
About esophagus cancer
Esophagus cancer is the fifth most common malignancy and the fourth leading cause of cancer mortality in China, accounting for nearly one in ten of all cancer deaths. Despite the fact that much progress has been made in diagnosis and systemic chemotherapy regimens, the overall prognosis of esophagus cancer is disappointing. The 5-year survival rate, all stages included, is around 15-25%. There remains a significant unmet medical need for esophagus cancer treatment.
Epitinib (HMPL-813) is a highly potent inhibitor of the EGFR tyrosine kinase involved in tumor growth, invasion and migration designed to maximise penetration of the drug into the brain. Epitinib has good kinase selectivity and demonstrated a broad spectrum of anti-tumor activity via oral dosing in multiple xenografts in preclinical studies. In preclinical studies, epitinib demonstrated excellent brain penetration and good efficacy in orthotopic brain tumor models and reached drug concentrations in the brain tissue that are expected to result in robust efficacy when given orally at doses well below toxic levels. The Phase I clinical trial started in China in mid-2011 showed it was well tolerated with excellent pharmacokinetic properties. It demonstrated the anti-tumor activity expected from EGFR inhibitors and partial response among patients with NSCLC with EGFR-activating mutation.
HMP is a novel drug R&D company focusing on discovering, developing and commercialising innovative therapeutics in oncology and autoimmune diseases. With a team of around 200 scientists and staff, its pipeline is comprised of novel oral compounds for cancer and inflammation in development in North America, Europe, Australia and Greater China. For more information, please visit: www.hmplglobal.com.