Savolitinib

Savolitinib (HMPL-504/AZD6094/volitinib) is a novel, small potent ATP-competitive c-Met inhibitor with high selectivity over a 274-kinase panel. It is being developed as tablet for the treatment of solid tumors.

HMPL-504 has been demonstrated to inhibit the growth of tumors in a series of preclinical disease models, selectively for those tumors with aberrant c-Met signalling. Phase I dose escalation studies were initiated in Australia and China in 2012 and 2013, respectively, and the first global Phase II study was initiated in 2014. HMPL-504 has demonstrated good safety and tolerability and favorable pharmacokinetic properties in late stage cancer patients, and has shown encouraging anti-tumor activity in several tumor-types, in particular for metastatic PRCC.

In December 2011, AstraZeneca and HMP have signed a global licensing, co-development, and commercialization agreement for HMPL-504.

In February 2012, HMP commenced the first-in-human phase I clinical trial of HMPL-504 in Australia which has progressed well through multiple dose levels and continues as a study of safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy against multiple tumor types, particularly among Caucasian patients.

In June 2013, HMP initiated the Phase I clinical trial of HMPL-504 in China. The primary objectives of the phase I study of HMPL-504 in China are to evaluate its safety and tolerability in patients in China with advanced cancer and to determine its maximum tolerated dose. The study will also evaluate Volitinib’s preliminary efficacy against various tumors, including lung cancer and gastric cancer, both being major unmet medical needs in China. The c-Met gene amplification status and protein expression levels will be evaluated to help inform subsequent patient selection strategies.

In May 2014, HMP and AstraZeneca initiated a global Phase II study to evaluate the efficacy and safety of HMPL-504 in patients with papillary renal cell carcinoma (PRCC). PRCC represents about 10 to 15% of all new cases of kidney cancer and advanced disease has no approved therapy today. Molecular alterations leading to aberrant activation of the c-Met signalling pathway have been well documented in PRCC and effective inhibition of c-Met has been considered a potential treatment pathway for PRCC.

This PRCC trial is an open-label, single-arm, multicenter, Phase II, study designed to evaluate the efficacy and safety of HMPL-504 in patients with locally advanced or metastatic PRCC. Approximately 20 centers in the United States, Canada, and Europe will participate in the study. The primary objective of this study is to assess the anti-tumor activity of HMPL-504 in patients with PRCC as measured by overall response rate according to Response Evaluation Criteria in Solid Tumors (“RECIST”) (version 1.1). The secondary objectives for this study are to: assess the progression free survival and duration of response in patients with PRCC according to RECIST (version 1.1); assess the safety and tolerability of HMPL-504 in the treatment of patients with PRCC; characterize the pharmacokinetics and pharmacodynamics of AZD6094 and metabolites following administration to steady state after multiple dosing when given orally; and obtain a preliminary assessment of HMPL-504 activity in blood and tumour by evaluation of biomarker changes which may include, but not limited to, phosphorylated c-Met. Exploratory objectives include an investigation of predictive markers and acquired resistance to HMPL-504 that may be observed in blood and tumor from patients treated with HMPL-504.