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London: Thursday, November 29, 2018: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) entered into four collaboration agreements to evaluate the safety, tolerability and efficacy of Chi-Med’s surufatinib (HMPL-012 or sulfatinib) and fruquintinib in combination with checkpoint inhibitors. It is an important part of Chi-Med’s strategy to explore the potential synergies of its drug candidates in combination with other anti-cancer treatments. These four new immunotherapy collaborations add to our ongoing studies combining savolitinib, Chi-Med’s highly selective c-Met inhibitor, with AstraZeneca PLC’s checkpoint inhibitor, durvalumab (Imfinzi^®).

Today, Chi-Med is announcing the first steps to develop its vascular endothelial growth factor receptor (“VEGFR”) inhibitors, surufatinib and fruquintinib, in combination with various programmed cell death protein-1 (“PD-1”) monoclonal antibodies in several solid tumor settings:

• A global collaboration to evaluate the combination of surufatinib with toripalimab (JS001), a PD-1 monoclonal antibody being developed by Shanghai Junshi Biosciences Co. Ltd.;

• A global collaboration to evaluate the combination of fruquintinib with sintilimab (IBI308), a PD-1 monoclonal antibody being developed by Innovent Biologics (Suzhou) Co. Ltd.;

• A collaboration in China to evaluate the combination of surufatinib with HX008, a PD-1 monoclonal antibody being developed by Taizhou Hanzhong Pharmaceuticals, Inc.; and

• A collaboration in China to evaluate the combination of fruquintinib with genolimzumab (GB226), a PD-1 monoclonal antibody being developed by Genor Biopharma Co. Ltd.

The global market for angiogenesis inhibitors was over US$18 billion in 2017, based on their use in around 30 different tumor settings. Each of the agreements announced today will pursue different initial indications within the field of solid tumors.

“Recent innovations in solid tumor drugs have focused on targeted therapies and immunotherapies which, as monotherapies, have both provided improved patients outcomes,” said Christian Hogg, Chief Executive Officer of Chi-Med. “We believe that the future of oncology treatments increasingly lies in combining therapies, utilizing multiple mechanisms of action (“MOA”) to confront tumors. Our unique next-generation anti-angiogenesis VEGFR inhibitors, with high selectivity and tolerability, make them ideal candidates for such combinations with immunotherapy agents such as PD-1/L1 monoclonal antibodies to prolong and expand the benefits of these therapies to more patients.”

Chi-Med’s proof-of-concept studies have already demonstrated the benefits of combinations with other kinase inhibitors or with chemotherapy.

Surufatinib (HMPL-012 or sulfatinib) is a novel, oral angio-immuno kinase inhibitor that inhibits 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. This dual angiogenesis-checkpoint inhibitor’s MOA may be very suitable for combination use with other immunotherapies. Surufatinib, as a monotherapy, is in late-stage clinical trials in China and began proof-of-concept clinical trials in the United States in July 2018.

Fruquintinib is a highly selective and potent oral inhibitor of VEGFR. Its unique kinase selectivity has been shown to reduce off-target toxicity thereby allowing possible use in combination with other agents. It was first approved for colorectal cancer in China in September 2018. It is in several late-stage clinical trials for lung and gastric cancer, including in combination with chemotherapy such as paclitaxel (Taxol^®) and other kinase inhibitors such as gefitinib (Iressa^®), and is in a Phase I clinical trial in the United States.

About Chi-Med

Chi-Med (AIM/Nasdaq: HCM) is an innovative biopharmaceutical company which researches, develops, manufactures and markets pharmaceutical products. Its Innovation Platform, Hutchison MediPharma, has about 400 scientists and staff focusing on discovering, developing and commercializing targeted therapeutics in oncology and autoimmune diseases. It has a portfolio of eight cancer drug candidates currently in clinical studies around the world. Chi-Med’s Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products, covering an extensive network of hospitals across China.

Dual-listed on the AIM market of the London Stock Exchange and the Nasdaq Global Select Market, Chi-Med is headquartered in Hong Kong and majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 1). For more information, please visit: www.chi-med.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of surufatinib and fruquintinib including as combination therapy with toripalimab, sintilimab, HX008 or genolimzumab; plans to initiate clinical studies for surufatinib and fruquintinib including as a combination therapy with toripalimab, sintilimab, HX008 or genolimzumab; its expectations as to whether such studies would meet their primary or secondary endpoints; and its expectations as to the timing of the enrollment completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of surufatinib and fruquintinib including as a combination therapy with toripalimab, sintilimab, HX008 or genolimzumab to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of surufatinib and fruquintinib including as a combination therapy with toripalimab, sintilimab, HX008 or genolimzumab for a targeted indication and the sufficiency of funding. In particular, as certain studies rely on the use of toripalimab, sintilimab, HX008 or genolimzumab as a combination therapeutic with surufatinib and fruquintinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and regulatory approval of toripalimab, sintilimab, HX008 or genolimzumab. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

CONTACTS

Investor Enquiries

Mark Lee, Senior Vice President, Corporate Finance & Development

+852 2121 8200

David Dible, Citigate Dewe Rogerson

+44 7967 566 919 (Mobile)

david.dible@citigatedewerogerson.com

Xuan Yang, Solebury Trout

+1 (415) 971 9412 (Mobile)

xyang@troutgroup.com

Media Enquiries

UK & Europe – Anthony Carlisle, Citigate Dewe Rogerson

+44 7973 611 888 (Mobile)

anthony.carlisle@cdrconsultancy.co.uk

Americas – Brad Miles, Solebury Trout

+1 (917) 570 7340 (Mobile)

bmiles@troutgroup.com

Hong Kong & Asia ex-China – Joseph Chi Lo, Brunswick

+852 9850 5033 (Mobile)

jlo@brunswickgroup.com

Hong Kong & Asia ex-China – Zhou Yi, Brunswick

+852 9783 6894 (Mobile)

yzhou@brunswickgroup.com

Mainland China – Sam Shen, Edelman

+86 1367 179 1029 (Mobile)

sam.shen@edelman.com

Nominated Advisor

Richard Gray / Andrew Potts, Panmure Gordon (UK) Limited

+44 (20) 7886 2500

London: Monday, July 23, 2018: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) has initiated a Phase Ib/II proof-of-concept study of sulfatinib in pancreatic neuroendocrine tumors (“NET”) patients and in biliary tract cancer (“BTC”) patients in the U.S..  Sulfatinib is an oral small molecule angio-immuno kinase inhibitor that can simultaneously block tumor angiogenesis and immune evasion.  This study follows several trials that are underway in China, including two Phase III studies in pancreatic and non-pancreatic NET that commenced after positive results from a Phase II study, and a Phase II study in BTC patients.  In addition, a Phase I dose escalation part of this study in the U.S. was recently completed.

This proof-of-concept study is a multi-center, single-arm, open-label study to evaluate the efficacy and safety of sulfatinib as a monotherapy in (a) patients with advanced BTC that have progressed on standard first-line chemotherapy, and (b) in patients with advanced pancreatic NET.  The primary and secondary endpoints include progression-free survival (“PFS”) rate, objective response rate (“ORR”), disease control rate (“DCR”), duration of response (“DoR”), time to response, overall survival (“OS”), safety and tolerability.  Additional details of the study may be found at clinicaltrials.gov, using identifier NCT02549937.

About Sulfatinib

Sulfatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (“VEGFR”), fibroblast growth factor receptor (“FGFR”) and colony stimulating factor-1 receptor (“CSF-1R”), three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion.  Inhibition of the VEGFR signaling pathway can act to stop angiogenesis, the growth of the vasculature around the tumor, and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly.  Aberrant activation of the FGFR signaling pathway, which can be increased by anti-VEGFR therapy treatment, is shown to be associated with cancer progression by promoting tumor growth, angiogenesis and formation of the myeloid derived suppressor cells.  Inhibition of the CSF-1R signaling pathway blocks the activation of tumor-associated macrophages, which are involved in suppressing immune responses against tumors.  Its unique angio-immuno kinase profile supports sulfatinib as a potentially attractive candidate for exploration of possible combinations with checkpoint inhibitors against various cancers.

Sulfatinib is the first oncology candidate that we have taken through proof-of-concept in China and subsequently started clinical development in the U.S.  We are currently conducting studies in six target patient populations on sulfatinib and retain all rights to sulfatinib worldwide.

About Sulfatinib Development in China

Sulfatinib is currently in development as a single agent for patients with NET, thyroid cancer and BTC in China.

Pancreatic NET:  In March 2016, we initiated the SANET-p study, which is a randomized, double-blind, placebo-controlled, multi-center, Phase III pivotal registration trial to treat about 190 patients with low- or intermediate-grade, advanced pancreatic NET in China.  The primary endpoint is PFS, with secondary endpoints including ORR, DCR, DoR, time to response, OS, safety and tolerability.  Additional details of the SANET-p study may be found at clinicaltrials.gov, using identifier NCT02589821.  We expect to complete enrollment in 2019 and present top-line results thereafter.

Extra-pancreatic NET:  The SANET-ep study, which was initiated in December 2015, is similar to the SANET-p study and is targeted at treating about 270 patients with advanced extra-pancreatic NET in China.  Additional details of the SANET-ep study may be found at clinicaltrials.gov, using identifier NCT02588170.  We expect to complete enrollment in 2019 and present top-line results thereafter.

Thyroid cancer:  In March 2016, we initiated Phase II in two target patient populations in China to evaluate the efficacy and safety of sulfatinib in patients with advanced medullary thyroid cancer and iodine-refractory differentiated thyroid cancer.  Additional details of this study may be found at clinicaltrials.gov, using identifier NCT02614495.

BTC:  In January 2017, we began a Phase II study in patients with BTC (also known as cholangiocarcinoma), a heterogeneous group of rare malignancies arising from the biliary tract epithelia.  Gemzar is the currently approved first-line therapy for biliary tract cancer patients, with a total of approximately 18,000 new patients per year in the U.S. according to the National Cancer Institute, but median survival is less than 12 months for patients with unresectable or metastatic disease at diagnosis. As a result, we see a major unmet medical need for patients who have progressed when being treated with Gemzar, and sulfatinib may offer a new targeted treatment option in this tumor type.  Additional details of this study may be found at clinicaltrials.gov, using identifier NCT02966821.

About Chi‑Med

Chi‑Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products.  Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi‑Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 1).  For more information, please visit: www.chi‑med.com.

Forward‑Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of sulfatinib, plans to initiate clinical studies for sulfatinib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidate sulfatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of sulfatinib for a targeted indication and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

CONTACTS

Investor Enquiries

Mark Lee, Senior Vice President,
Corporate Finance & Development
+852 2121 8200

U.K. & International Media Enquiries

Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk

U.S. Based Media Enquiries

Brad Miles, Solebury Trout
+1 (917) 570 7340 (Mobile)
bmiles@troutgroup.com

Susan Duffy, Solebury Trout
+1 (917) 499 8887 (Mobile)
sduffy@troutgroup.com

Investor Relations

Xuan Yang, Solebury Trout
+1 (415) 971 9412 (Mobile)
xyang@troutgroup.com

David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedewerogerson.com

Panmure Gordon (UK) Limited

Richard Gray / Andrew Potts
+44 (20) 7886 2500

 

 

A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC)

Venue: American Society of Clinical Oncology Annual Meeting  in Chicago, Illinois, USA

Abstract #: 6037

Authors: J Chen, Q Ji, J Cao, D Ji, C Bai, Y Lin, B Pan, G Sun, J Li, C Qi, Y Hua

Session: Head and Neck Cancer

Date & Time: Monday, June 5, 2017, 1:15 PM CDT

Location: Hall A

Press Release

– FRESCO Phase III trial results for fruquintinib in colorectal cancer in an oral presentation –

– Five abstracts in total accepted for fruquintinib, savolitinib and sulfatinib –

London: Thursday, May 18, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that new clinical data on three of its novel tyrosine kinase inhibitors, fruquintinib, savolitinib and sulfatinib, will be presented at the 2017 American Society of Clinical Oncology (“ASCO”) Annual Meeting, to be held in Chicago, Illinois from June 2 to 6, 2017.

The five presentations, one oral presentation and four poster presentations, cover the following studies:

Fruquintinib:

• The full results of the FRESCO Phase III study in 416 patients with locally advanced or metastatic colorectal cancer (“CRC”) will be highlighted in an oral presentation on June 5, 2017. Primary endpoint median overall survival was 9.30 months for fruquintinib versus 6.57 months in the control group, with a hazard ratio of 0.65 and p< 0.001. Fruquintinib was well tolerated, with manageable on-target treatment related adverse events consistent with previous studies.

Savolitinib:

• c-MET amplification (“amp”) is a major acquired resistance (“AR”) pathway to Tagrisso^® (osimertinib). AstraZeneca PLC (“AstraZeneca”) will highlight an analysis of 23 EGFR-mutant non-small-cell lung cancer (“NSCLC”) patients with AR to Tagrisso®. Analysis shows that about 30% (7/23 patients) of AR is c-MET amp and that among the 7 patients with c-MET amp, 3 patients received combination Tagrisso^®/savolitinib therapy; all 3 had partial response (“PR”) under RECIST (Response Evaluation Criteria in Solid Tumors) guidelines.

• Savolitinib included in PAPMET Phase II study (sponsored by NIH/NCI) of multiple c-MET and vascular endothelial growth factor receptor (“VEGFR”) tyrosine kinase inhibitors in metastatic papillary renal cell carcinoma patients. PAPMET will evaluate four therapies in a 1:1:1:1 randomization, sunitinib, cabozantinib, crizotinib and savolitinib in an about 275-patient study which began in 2016 and as at January 30, 2017 had registered 26 patients. PAPMET will study efficacy, safety and correlation of clinical outcome with tumor molecular driver alterations such as c-MET.

• Update on the VIKTORY trial, a biomarker-based umbrella trial in gastric cancer. From June 2014 to January 2017, a total of 432 metastatic gastric cancer patients were enrolled in VIKTORY, a total of 23 patients (5.3%) were guided into savolitinib monotherapy treatment (4/23 patients) or savolitinib/docetaxel combination therapy (19/23) based on molecular screening outcomes.

Sulfatinib:

• Preliminary results of a Phase II study in advanced medullary thyroid cancer (“MTC”) and radioiodine (“RAI”)-refractory differentiated thyroid cancer (“DTC”). Sulfatinib is an oral, novel angio-immuno kinase inhibitor that selectively targets VEGFR, fibroblast growth factor receptor-1 (“FGFR”) and colony-stimulating factor-1 receptor (“CSF-1R”). As at December 31, 2016 a total of 18 patients had been enrolled with 1/6 MTC patients and 3/12 RAI-DTC patients reporting confirmed PRs, and all other patients stable disease, under RECIST.

Presentation Details

Abstracts for the presentations are available at abstracts.asco.org, as listed below:

Fruquintinib:

Title: A randomized, double-blind, placebo-controlled, multi-centered phase III trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (FRESCO)

Abstract #: 3508

Presenter: Dr. Jin Li, Oncologist and Director of the Tumor Department, Shanghai East Hospital, Tongji University School of Medicine

Authors: J Li, S Qin, RH Xu, J Xu, L Shen, Y Bai, Y Deng, L Yang, ZD Chen, H Zhong, H Pan, W Guo, Y Shu, Y Yuan, J Zhou

Session: Gastrointestinal (Colorectal) Cancer – Oral Abstract Session

Date & Time: Monday, June 5, 2017, 5:24 PM CDT

Location: Hall D2

 

Savolitinib:

Title: MET amplification (amp) as a resistance mechanism to osimertinib

Abstract #: 9020

Authors: Z Piotrowska, K Thress, M Mooradian, RS Heist, CG Azzoli, J Temel, C Rizzo, R Nagy, R Lanman, S Gettinger, T Evans, A Hata, A Shaw, LV Sequist

Session: Lung Cancer—Non-Small Cell Metastatic

Date & Time: Saturday, June 3, 08:00 – 11:30 AM CDT

Location: Hall A

Title: A randomized, phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma (PRCC): SWOG S1500

Abstract #: TPS4599

Authors: SK Pal, C Tangen, IM Thompson, B Shuch, NB Haas, DJ George, M Stein, M Plets, PN Lara

Session: Genitourinary (Nonprostate) Cancer

Date & Time: Sunday, June 4, 08:00 – 11:30 AM CDT

Location: Hall A

Title: VIKTORY trial: Report on AZD1775/paclitaxel in TP53 mutation (+) GC, selumetinib/paclitaxel in ras aberrant GC, AZD5363/paclitaxel in PIK3CA mt and biomarker negative, savolitinib/docetaxel in met (+), and vistusertib/paclitaxel in RICTOR(+) GC

Abstract #: 4024

Authors: J Lee, ST Kim, PG Mortimer, S Hollingsworth, E Harrington, C Shepherd, E Kilgour, SH Park, H Lee, SY Oh, JH Kang, JO Park, YS Park, HY Lim, KM Kim, WK Kang

Session: Gastrointestinal (Noncolorectal) Cancer

Date & Time: Saturday, June 3, 08:00 – 11:30 AM CDT

Location: Hall A

 

Sulfatinib:

Title: A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC)

Abstract #: 6037

Authors: J Chen, Q Ji, J Cao, D Ji, C Bai, Y Lin, B Pan, G Sun, J Li, C Qi, Y Hua

Session: Head and Neck Cancer

Date & Time: Monday, June 5, 1:15 PM CDT

Location: Hall A

 

Once presented, the presentations will be available at www.chi-med.com/news/. Further information about ASCO is available at asco.org.

 

About Fruquintinib

Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, without known off-target toxicities. Its tolerability, along with its clean drug-drug interaction profile, enables rational combination with other cancer therapies such as in our ongoing clinical trials of fruquintinib in combination with chemotherapy and targeted therapy.

At an advanced stage, tumors secrete large amounts of VEGF, a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGFR play a pivotal role in tumor-related angiogenesis, and the inhibition of the VEGF/VEGFR pathway. This represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Fruquintinib is currently under joint development in China by Chi-Med and its partner Eli Lilly and Company (“Lilly”). Chi-Med and Lilly jointly announced top-line results from the FRESCO CRC trial on March 3, 2017. In addition, fruquintinib is being studied in China in a Phase III pivotal trial in NSCLC, known as FALUCA; and a Phase II study using fruquintinib combined with Iressa^® (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the United States, and certain exploratory studies in combination with other oncology agents.

 

About Savolitinib

Savolitinib (AZD6094/HMPL-504) is a potential global first-in-class inhibitor of c-MET (also known as mesenchymal epithelial transition factor) receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumors. It was developed as a potent and highly selective oral inhibitor specifically designed to address issues observed in the clinic with first-generation c-MET inhibitors, including renal toxicity.

Savolitinib was discovered by Chi-Med and is being developed in collaboration with AstraZeneca. AstraZeneca and Chi-Med are currently testing savolitinib in multiple tumor types worldwide including kidney, lung and gastric cancers, both as a monotherapy or in combination with other targeted and immunotherapy agents.

 

About Sulfatinib

Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively inhibits the tyrosine kinase activity associated with VEGFR, FGFR and CSF-1R, three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion. Inhibition of the VEGFR signaling pathway can act to stop angiogenesis, the growth of the vasculature around the tumor, and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly. Aberrant activation of the FGFR signaling pathway, which can be increased by anti-VEGFR therapy treatment, is shown to be associated with cancer progression by promoting tumor growth, angiogenesis and formation of the myeloid derived suppressor cells. Inhibition of the CSF-1R signaling pathway blocks the activation of tumor-associated macrophages, which are involved in suppressing immune responses against tumors.

Six sulfatinib clinical trials are underway in China and the United States, including two Phase III studies and one Phase II study in neuroendocrine tumors patients (SANET-p, SANET-ep and SANET-1), one Phase II study in thyroid cancer patients and one Phase II study in biliary tract cancer patients.

 

About Chi-Med

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of fruquintinib, savolitinib and sulfatinib, plans to initiate clinical studies for fruquintinib, savolitinib and sulfatinib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidates fruquintinib, savolitinib and sulfatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of fruquintinib, savolitinib and sulfatinib for a targeted indication and the sufficiency of funding. In addition, as certain studies rely on the use of Iressa^® (gefitinib) as a combination therapeutic with fruquintinib and docetaxel and Tagrisso^® (osimertinib) as a combination therapeutic with savolitinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of Iressa^®, docetaxel and Tagrisso^®. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

 

CONTACTS

Investor Enquiries

Christian Hogg, CEO +852 2121 8200

U.K. & International Media Enquiries

Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk

U.S. Based Media Enquiries

Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com

Susan Duffy, BMC Communications
+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com

Investor Relations

Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com

David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk

Panmure Gordon (UK) Limited

Richard Gray / Andrew Potts +44 (20) 7886 2500

London: Friday, April 7, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) presented pre-clinical data for fruquintinib and sulfatinib at the American Association for Cancer Research (“AACR”) Annual Meeting 2017, held in Washington, D.C., USA from April 1 to 5, 2017. Fruquintinib and sulfatinib are both being evaluated in Phase III clinical trials for various cancers.

Fruquintinib is designed to be a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (“VEGFR”) with a tolerability profile that enables rational combination with other cancer therapies. A new drug application (“NDA”) for fruquintinib to the China Food and Drug Administration (“CFDA”) is expected to be filed in mid-2017. It is currently under the joint development in China by Chi-Med and its partner Eli Lilly and Company (“Lilly”).

Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively targets VEGFR, fibroblast growth factor receptor (“FGFR”) and colony-stimulating factor-1 receptor (“CSF 1R”), three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion. Two Phase III trials are underway in neuroendocrine tumor (“NET”) patients in China.

The presentations were as follows:

 

Presentation Title: Evaluation of fruquintinib, a potent and selective oral VEGFR inhibitor, in combination with targeted therapies or immune checkpoint inhibitors in preclinical tumor models

Authors: Yongxin Ren et al.

Abstract: #2089

Session: Growth Factor and Hormone Receptors as Therapeutic Targets

Date & Time: Monday, April 3, 2017, 1:00 PM (EST)

 

Presentation Title: Preclinical evaluation of sulfatinib, a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF-1R kinases

Authors: Jinghong Zhou et al.

Abstract: #4187

Session: Targeting Protein Kinases and DNA Repair

Date & Time: Tuesday, April 4, 2017, 1:00 PM (EST)

 

The presentations are available at www.chi-med.com/news/. Further information about AACR is available at aacr.org.

 

ABSTRACTS

Evaluation of fruquintinib, a potent and selective oral VEGFR inhibitor, in combination with targeted therapies or immune checkpoint inhibitors in preclinical tumor models

Authors: Yongxin Ren, Qiaoling Sun, Jingwen Long, Shiming Fan, Renxiang Tang, Wei Zhang, Xuelei Ge, Jianxing Tang, Linfang Wang, Dongxia Shi, Hongbo Chen, Min Cheng, Weiguo Qing and Weiguo Su

The development of therapies targeting tumor angiogenesis, tumor driver gene alterations and tumor immune evasion has made tremendous advancement in improving overall survival (“OS”). However, efficacy may be limited and resistance often develops rapidly when targeting a single axis of tumorigenesis. Therefore, it is worthwhile to explore rational combination of therapies based on tumor-specific features. Fruquintinib is a potent and selective oral VEGFR inhibitor currently in Phase III clinical trials for non-small-cell lung cancer (“NSCLC”) and colorectal cancer (“CRC”). We report here the evaluation of anti-tumor effect of fruquintinib in preclinical animal tumor models in combination with therapies targeting tumor driver gene alterations such as epidermal growth factor receptor (“EGFR”) and mesenchymal growth factor receptor (“c-MET”) or with immune checkpoints.

In NSCLC xenograft models with EGFR activation such as activating mutations, gene amplification or protein overexpression, fruquintinib plus an EGFR tyrosine kinase inhibitor such as gefitinib or theliatinib (HMPL-309) was found to be more efficacious than either monotherapy. For instance, in PC-9 subcutaneous tumor model carrying EGFR exon 19 deletion, single agent treatment with fruquintinib at 2 mg/kg and gefitinib at 5 mg/kg produced the tumor growth inhibition (“TGI”) of 58% and 63%, respectively, while the combination treatment resulted in a TGI of 100% and tumor regression was observed in 11 of 16 mice treated with combinational therapy. In multiple xenograft models derived from lung cancer or renal cell cancer with c-MET activation (amplification or over-expression), addition of fruquintinib to a c-MET inhibitor savolitinib (AZD6094, HMPL-504) also improved the tumor growth inhibition substantially. At the end of the efficacy studies, CD31 and phosphorylation of EGFR, c-MET, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) were analyzed with immunohistochemistry and western blotting method in tumor tissues. The results suggested that the enhanced anti-tumor effect in combination therapy could be attributed to the simultaneous blockade of cell signaling in tumor cells (EGFR or c-MET) and VEGFR suppression in the tumor microenvironment.

Up-regulation of the immune inhibitory checkpoints induced by vascular endothelial growth factor (“VEGF”) is one of the important mechanisms for tumor cells to escape immune surveillance. In a syngeneic murine tumor model, co-administration of fruquintinib and anti-Programmed death-ligand 1 (“PD-L1”) antibody was found to provide improved anti-tumor effect compared to fruquintinib or anti-PD-L1 single agent alone. Studies to understand the mechanism responsible for the combination effect are underway.

All combinations with fruquintinib described above were well tolerated. The efficacy observed in these models suggested that simultaneous blockade of tumor angiogenesis and tumor cell signaling or immune evasion may be a promising approach in improving treatment outcomes.

 

Preclinical evaluation of sulfatinib, a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF-1R kinases

Authors: Jinghong Zhou, Jun Ni, Min Cheng, Na Yang, Junqing Liang, Liang Ge, Wei Zhang, Jianxing Tang, Qiaoling Sun, Fu Li, Jia Hu, Dongxia Shi, Hongbo Chen, Jingwen Long, Junen Sun, Fang Yin, Xuelei Ge, Hong Jia, Feng Zhou, Yongxin Ren, Weiguo Qing and Weiguo Su

Both VEGFR and FGFR signaling pathways can mediate tumor angiogenesis. CSF-1R plays an important role on functions of macrophages. Recently, the roles in increasing tumor immune evasion of VEGFR, FGFR in regulation of T cells, tumor-associated macrophages (“TAMs”) and myeloid-derived suppressor cells have been demonstrated. Therefore, blockade of tumor angiogenesis and tumor immune evasion by simultaneously targeting VEGFR, FGFR and CSF-1R kinases may represent a promising approach for anti-cancer therapy.

We report here the preclinical studies for sulfatinib (HMPL-012), a potent and highly selective small molecule tyrosine kinase inhibitor against VEGFR, FGFR1 and CSF-1R. Sulfatinib inhibited VEGFR1, 2, and 3, FGFR1 and CSF-1R kinases with IC50s in a range of 1~24 nM, and it strongly blocked VEGF induced VEGFR2 phosphorylation in HEK293KDR cells and colony-stimulating factor-1 stimulated CSF-1R phosphorylation in RAW264.7 cells with IC50 of 2 and 79 nM, respectively. Sulfatinib also attenuated VEGF or FGF stimulated HUVEC cells proliferation with IC50 < 50 nM. In animal studies, a single oral dosing of sulfatinib inhibited VEGF stimulated VEGFR2 phosphorylation in lung tissues of nude mice in an exposure-dependent manner. Furthermore, elevation of FGF23 levels in plasma 24 hours post dosing suggested suppression of FGFR signaling. Sulfatinib demonstrated potent tumor growth inhibition in multiple human xenograft models and decreased CD31 expression remarkably, suggesting strong inhibition on angiogenesis through VEGFR and FGFR signaling. In a syngeneic murine colon cancer model CT-26, sulfatinib demonstrated moderate tumor growth inhibition after single agent treatment. Flow cytometry and immunohistochemistry analysis revealed an increase of CD8+ T cells and a significant reduction in TAMs, (CD163+ or F4/80+CD11b+CD45+) and CSF-1R+ TAMs in tumor tissue indicating strong effect on CSF-1R. Interestingly, combination of sulfatinib with a PD-L1 antibody resulted in enhanced anti-tumor effect. These results suggested that sulfatinib has a strong effect in modulating angiogenesis and cancer immunity.

In summary, sulfatinib is a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF-1R kinases that could simultaneously block tumor angiogenesis and immune evasion. This unique feature seems to support sulfatinib as an attractive candidate for exploration of possible combinations with checkpoint inhibitors against various cancers. Sulfatinib is currently in multiple clinical trials including two Phase III trials against neuroendocrine tumors.

 

About Fruquintinib

Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, without known off-target toxicities. At an advanced stage, tumors secrete large amounts of VEGF, a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGFR play a pivotal role in tumor-related angiogenesis, and the inhibition of the VEGF/VEGFR pathway. This represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Fruquintinib is currently under joint development in China by Chi-Med and its partner Lilly. In early March, Chi-Med and Lilly jointly announced top-line results from FRESCO, the Phase III pivotal registration trial of fruquintinib in 416 patients with locally advanced or metastatic CRC in China, who failed at least two prior chemotherapies, including fluoropyrimidine, oxaliplatin and irinotecan. The FRESCO trial met its primary endpoint of demonstrating a clinically meaningful and a statistically significant increase in OS in the intention-to-treat (“ITT”) population of patients treated with fruquintinib plus best supportive care (“BSC”) as compared to patients treated with placebo plus BSC. Chi-Med is currently preparing to submit an NDA for fruquintinib to the CFDA. In addition to OS, a statistically significant improvement in progression-free survival (“PFS”), a key secondary endpoint, was observed. The adverse events demonstrated in FRESCO did not identify any new or unexpected safety issues. Full detailed results are subject to ongoing analysis and are expected to be disclosed at an upcoming scientific meeting in mid-2017.

In addition to the FRESCO CRC trial, fruquintinib is being studied in China in a Phase III pivotal trial in NSCLC, known as FALUCA; and a Phase II study using fruquintinib combined with Iressa® (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the United States, and certain exploratory studies in combination with other oncology agents.

 

About Sulfatinib

Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively inhibits the tyrosine kinase activity associated with VEGFR, FGFR and CSF-1R, three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion. Inhibition of the VEGFR signaling pathway can act to stop angiogenesis, the growth of the vasculature around the tumor, and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly. Aberrant activation of the FGFR signaling pathway, which can be increased by anti-VEGFR therapy treatment, is shown to be associated with cancer progression by promoting tumor growth, angiogenesis and formation of the myeloid derived suppressor cells. Inhibition of the CSF-1R signaling pathway blocks the activation of tumor-associated macrophages, which are involved in suppressing immune responses against tumors.

Six sulfatinib clinical trials are underway in China and the United States, including two Phase III studies and one Phase II study in NET patients (SANET-p, SANET-ep and SANET-1), one Phase II study in thyroid cancer patients and one Phase II study in biliary tract cancer patients.

 

About Chi-Med

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995. These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of fruquintinib or sulfatinib, plans to initiate clinical studies for fruquintinib or sulfatinib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidates fruquintinib or sulfatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of fruquintinib or sulfatinib for a targeted indication and the sufficiency of funding. In addition, as certain studies rely on the use of Iressa® as a combination therapeutic with fruquintinib, such risks and uncertainties include assumptions regarding the safety, efficacy, supply and continued regulatory approval of Iressa®. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

 

CONTACTS

Investor Enquiries
Christian Hogg, CEO
+852 2121 8200

U.K. & International Media Enquiries
Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk

U.S. Based Media Enquiries
Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com
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+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com

Investor Relations
Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com
David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk

Panmure Gordon (UK) Limited
Richard Gray / Andrew Potts
+44 (20) 7886 2500

Preclinical evaluation of sulfatinib, a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF-1R kinases

Authors: Jinghong Zhou, Jun Ni, Min Cheng, Na Yang, Junqing Liang, Liang Ge, Wei Zhang, Jianxing Tang, Qiaoling Sun, Fu Li, Jia Hu, Dongxia Shi, Hongbo Chen, Jingwen Long, Junen Sun, Fang Yin, Xuelei Ge, Hong Jia, Feng Zhou, Yongxin Ren, Weiguo Qing and Weiguo Su

Both VEGFR and FGFR signaling pathways can mediate tumor angiogenesis. CSF-1R plays an important role on functions of macrophages. Recently, the roles in increasing tumor immune evasion of VEGFR, FGFR in regulation of T cells, tumor-associated macrophages (“TAMs”) and myeloid-derived suppressor cells have been demonstrated. Therefore, blockade of tumor angiogenesis and tumor immune evasion by simultaneously targeting VEGFR, FGFR and CSF-1R kinases may represent a promising approach for anti-cancer therapy.

We report here the preclinical studies for sulfatinib (HMPL-012), a potent and highly selective small molecule tyrosine kinase inhibitor against VEGFR, FGFR1 and CSF-1R. Sulfatinib inhibited VEGFR1, 2, and 3, FGFR1 and CSF-1R kinases with IC₅₀s in a range of 1~24 nM, and it strongly blocked VEGF induced VEGFR2 phosphorylation in HEK293^KDR cells and colony-stimulating factor-1 stimulated CSF-1R phosphorylation in RAW264.7 cells with IC₅₀ of 2 and 79 nM, respectively. Sulfatinib also attenuated VEGF or FGF stimulated HUVEC cells proliferation with IC50 < 50 nM. In animal studies, a single oral dosing of sulfatinib inhibited VEGF stimulated VEGFR2 phosphorylation in lung tissues of nude mice in an exposure-dependent manner. Furthermore, elevation of FGF23 levels in plasma 24 hours post dosing suggested suppression of FGFR signaling. Sulfatinib demonstrated potent tumor growth inhibition in multiple human xenograft models and decreased CD31 expression remarkably, suggesting strong inhibition on angiogenesis through VEGFR and FGFR signaling. In a syngeneic murine colon cancer model CT-26, sulfatinib demonstrated moderate tumor growth inhibition after single agent treatment. Flow cytometry and immunohistochemistry analysis revealed an increase of CD8+ T cells and a significant reduction in TAMs, (CD163+ or F4/80+CD11b+CD45+) and CSF-1R+ TAMs in tumor tissue indicating strong effect on CSF-1R. Interestingly, combination of sulfatinib with a PD-L1 antibody resulted in enhanced anti-tumor effect. These results suggested that sulfatinib has a strong effect in modulating angiogenesis and cancer immunity.

In summary, sulfatinib is a novel angio-immuno kinase inhibitor targeting VEGFR, FGFR1 and CSF-1R kinases that could simultaneously block tumor angiogenesis and immune evasion. This unique feature seems to support sulfatinib as an attractive candidate for exploration of possible combinations with checkpoint inhibitors against various cancers. Sulfatinib is currently in multiple clinical trials including two Phase III trials against neuroendocrine tumors.

Press Release

London: Friday, March 10, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) presented data from the ongoing Phase Ib/II clinical trial of sulfatinib in patients with advanced neuroendocrine tumors (“NET”) at the 14^th Annual Conference of the European Neuroendocrine Tumor Society (“ENETS”), held in Barcelona, Spain from March 8 to 10, 2017.  Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively targets vascular endothelial growth factor receptor (“VEGFR”), fibroblast growth factor receptor (“FGFR”) and colony-stimulating factor-1 receptor (“CSF-1R”), three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion.  Five other sulfatinib clinical trials are underway in China and the U.S., including two Phase III studies in NET patients (SANET-p and SANET-ep), one Phase II study in thyroid cancer patients and one Phase II study in biliary tract cancer patients.

The most recent results of the study were presented in detail as follows:

Presentation Type: Oral Presentation, Presidential Abstract – Plenary Meeting Room

Title: An Open-Label Phase Ib/II Study of Sulfatinib in Patients with Advanced Neuroendocrine Tumors (NCT02267967)

Presented by: Dr. JianMing Xu

Session: Session 2B: Medical Therapies and Goals

Date & Time: Thursday, March 9, 2017, 11:10 AM CET

 

Presentation summary

The current Phase Ib/II trial is an open-label, single-arm Phase II study to assess the efficacy and safety of sulfatinib monotherapy in patients with advanced grade 1 or 2 advanced NET.  81 patients (41 pancreatic NET and 40 extra-pancreatic NET) were enrolled between November 2014 and January 2016, in seven clinical centers across China.  The majority of patients had grade 2 disease (79%) and had failed previous systemic treatments (65%).  As of January 20, 2017, 13 patients had confirmed partial response (“PR”) and 61 patients had stable disease (“SD”) corresponding to an overall objective response rate (“ORR”) of 16.0% (13/81), with 17.1% (7/41) in pancreatic NET and 15.0% (6/40) in extra-pancreatic NET, and an overall disease control rate (“DCR”) of 91.4%.  Median overall progression-free survival (“PFS”) has not been reached, but is estimated to be 16.6 months (95% CI: 13.4, 19.4) with longer median PFS in pancreatic NET estimated at 19.4 months and shorter median PFS in extra-pancreatic NET estimated at 13.4 months.  Importantly, there were 12 patients who had progressed after treatment with targeted therapies (e.g. Sutent^® and Afinitor^®) and all benefited from sulfatinib treatment (3 PRs and 9 SDs).  Sulfatinib was well tolerated with Grade ≥3 adverse events (AEs), with >5% incidence, regardless of causality of hypertension (31%), proteinuria (14%), hyperuricemia (10%), hypertriglyceridemia (9%), diarrhea (7%) and ALT increase (6%).  Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02267967.

Based on the promising Phase I and Phase II efficacy data and tolerability in patients with advanced NETs, two randomized Phase III trials are ongoing.

The presentation is available at www.chi-med.com/news/.  Further information about ENETS is available at enetsconference.org.

 

 

About NET

NET arises from neuroendocrine cells and develop predominantly in the digestive or respiratory tracts but can also occur in many areas of the body.  Diagnosis of NET is difficult due to the small tumor size and diverse origination with patients showing varied or no symptoms.  There were approximately 20,000 new cases of NET and a cumulative prevalence of approximately 148,000 cases in the U.S. in 2016[1].

NETs can be classified according to tumor origin, as pancreatic NET representing less than 10% of the total NET patients, and extra-pancreatic NET comprising all other non-pancreatic NETs including lung, lymph and gastrointestinal tract NETs.  To date, treatment options for NET patients are limited; sunitinib and everolimus are the only two approved targeted-therapies for NET, sunitinib for pancreatic NET and everolimus for NET of pancreatic, gastrointestinal or lung origin, while there is no such a choice for broad spectrum NET patients.

 

About Sulfatinib

Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively inhibits the tyrosine kinase activity associated with VEGFR, FGFR and CSF-1R, three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion.  Inhibition of the VEGFR signaling pathway can act to stop angiogenesis, the growth of the vasculature around the tumor, and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly.  Aberrant activation of the FGFR signaling pathway, which can be increased by anti-VEGFR therapy treatment, is shown to be associated with cancer progression by promoting tumor growth, angiogenesis and formation of the myeloid derived suppressor cells.  Inhibition of the CSF-1R signaling pathway blocks the activation of tumor-associated macrophages, which are involved in suppressing immune responses against tumors.

In addition to the current Phase Ib/II NET trial, five sulfatinib clinical trials are underway in China and the U.S., including two Phase III studies in NET patients (SANET-p and SANET-ep), one Phase II study in thyroid cancer patients and one Phase II study in biliary tract cancer patients.

The SANET-p trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III pivotal registration trial to treat about 190 pathologically low or intermediate grade pancreatic NET patients in China whose disease has progressed, locally advanced or distant metastasized and for whom there is no effective therapy.  The primary endpoint is PFS, with secondary endpoints including ORR, DCR, duration of response (“DoR”), time to response and overall survival (“OS”).  Additional details of the SANET-p study may be found at clinicaltrials.gov, using identifier NCT02589821.  The SANET-ep trial is similar to the SANET-p trial and is targeted at treating about 270 non-pancreatic NET patients in China.  Additional details of the SANET-ep study may be found at clinicaltrials.gov, using identifier NCT02588170.

Chi-Med is conducting an open-label Phase II clinical trial to evaluate the efficacy and safety of sulfatinib in about 50 patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer or medullary thyroid cancer in China.  The primary endpoint is ORR, with secondary endpoints including safety and tolerability, DCR, time to response and PFS.  Additional details of this study may be found at clinicaltrials.gov, using identifier NCT02614495.

Chi-Med is also conducting an open-label Phase II clinical trial to evaluate the efficacy and safety of sulfatinib in about 32 patients with advanced or metastatic biliary tract cancer who failed one prior systemic therapy in China.  The primary endpoint is PFS at 16 weeks, with secondary endpoints including the ORR, DCR, DoR, PFS, OS and safety.  Additional details of this study may be found at clinicaltrials.gov, using identifier NCT02966821.

 

About Chi-Med

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products.  Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995.  These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of sulfatinib, including plans for further clinical studies of sulfatinib in NET, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidate sulfatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of sulfatinib for a targeted indication and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.  For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. 

 

CONTACTS

Christian Hogg, CEO
+852 2121 8200

U.K. and International Media Enquiries

Anthony Carlisle, Citigate Dewe Rogerson
+44 7973 611 888 (Mobile)
anthony.carlisle@cdrconsultancy.co.uk

U.S. Based Media Enquiries

Brad Miles, BMC Communications
+1 (917) 570 7340 (Mobile)
bmiles@bmccommunications.com

Susan Duffy, BMC Communications
+1 (917) 499 8887 (Mobile)
sduffy@bmccommunications.com

Investor Relations

Matt Beck, The Trout Group
+1 (917) 415 1750 (Mobile)
mbeck@troutgroup.com

David Dible, Citigate Dewe Rogerson
+44 7967 566 919 (Mobile)
david.dible@citigatedr.co.uk

Panmure Gordon (UK) Limited

Richard Gray / Andrew Potts
+44 (20) 7886 2500

 

[1] According to Frost & Sullivan.

An Open-Label Phase Ib/II Study of Sulfatinib in Patients with Advanced Neuroendocrine Tumors (NCT02267967)

Authors: J.M. Xu, J. Li, C.M. Bai, N. Xu, Z.W. Zhou, Z.P. Li, C.C. Zhou, W. Wang, J. Li, C. Qi, Y. Hua, W.G. Su

Summary: The current Phase Ib/II trial is an open-label, single-arm Phase II study to assess the efficacy and safety of sulfatinib monotherapy in patients with advanced grade 1 or 2 advanced NET.  81 patients (41 pancreatic NET and 40 extra-pancreatic NET) were enrolled between November 2014 and January 2016, in seven clinical centers across China.  The majority of patients had grade 2 disease (79%) and had failed previous systemic treatments (65%).  As of January 20, 2017, 13 patients had confirmed partial response (“PR”) and 61 patients had stable disease (“SD”) corresponding to an overall objective response rate (“ORR”) of 16.0% (13/81), with 17.1% (7/41) in pancreatic NET and 15.0% (6/40) in extra-pancreatic NET, and an overall disease control rate (“DCR”) of 91.4%.  Median overall progression-free survival (“PFS”) has not been reached, but is estimated to be 16.6 months (95% CI: 13.4, 19.4) with longer median PFS in pancreatic NET estimated at 19.4 months and shorter median PFS in extra-pancreatic NET estimated at 13.4 months.  Importantly, there were 12 patients who had progressed after treatment with targeted therapies (e.g. sunitinib and everolimus) and all benefited from sulfatinib treatment (3 PRs and 9 SDs).  Sulfatinib was well tolerated with Grade ≥3 adverse events (AEs) with >5% incidence, regardless of causality, of hypertension (31%), proteinuria (14%), hyperuricemia (10%), hypertriglyceridemia (9%), diarrhea (7%) and ALT increase (6%).  Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02267967.

Based on the promising Phase I and Phase II efficacy data and tolerability in patients with advanced NETs, two randomized Phase III trials are ongoing.

 

Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: results from a phase I study

 

Authors: Jian Ming Xu, Yan Wang, Yu Ling Chen, Ru Jia, Jie Li, Ji Fang Gong, Jing Li, Chuan Qi, Ye Hua, Cui Rong Tan, Jian Wang, Ke Li, Yang Sai, Feng Zhou, Yong Xin Ren, Wei Guo Qing, Hong Jia, Wei Guo Su and Lin Shen

Citation: Oncotarget 2017 Jun 27;8(26):42076-42086.

DOI: 10.18632/oncotarget.14942

PubMed ID: 28159938

Abstract:

Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation.

This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules).

Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea.

Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34).

Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

London: Monday, January 16, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that it has initiated a Phase II study of sulfatinib in second-line biliary tract cancer (“BTC”) patients in China.  Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively targets vascular endothelial growth factor receptor (“VEGFR”), fibroblast growth factor receptor (“FGFR”) and colony-stimulating factor-1 receptor (“CSF-1R”), three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion.  The first drug dose was administered on January 9, 2017.

This Phase II study is a multi-center, single-arm, open-label study to evaluate the efficacy and safety of sulfatinib as a monotherapy in treating advanced or metastatic BTC patients who failed one prior systemic therapy.  The primary endpoint is progression free survival (“PFS”) at 16 weeks, with secondary endpoints including objective response rate (“ORR”), disease control rate (“DCR”), duration of response, PFS, overall survival (“OS”) and safety.  Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02966821.

About BTC

BTC, also known as cholangiocarcinoma, is a heterogeneous group of rare but fatal malignancies arising from the biliary tract epithelia, including intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.  BTC is the second most frequently occurring type of liver cancer in the world, after hepatocellular carcinoma (HCC), accounting for approximately 15% of all liver cancer cases[1].  In 2017, there will be approximately 18,000 new BTC cases in the United States, according to the National Cancer Institute.  However, in China, the incidence can be up to 40 times the rate observed in the Western world[2].

Gemcitabine is the current first-line therapy for BTC patients, either as a monotherapy or in combination with cisplatin, and there is no established second-line therapy for this fatal disease worldwide.  The median life expectancy is less than 12 months for patients with unresectable or metastatic disease at diagnosis.  Accordingly, we see a high unmet medical need for new targeted treatment options.

About Sulfatinib

Sulfatinib is an oral, novel angio-immunokinase inhibitor that selectively inhibits the tyrosine kinase activity associated with VEGFR, FGFR and CSF-1R, three key tyrosine kinase receptors involved in tumor angiogenesis and immune evasion.  Inhibition of the VEGFR signaling pathway can act to stop angiogenesis, the growth of the vasculature around the tumor, and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly.  Aberrant activation of the FGFR signaling pathway, which can be increased by anti-VEGFR therapy treatment, is shown to be associated with cancer progression by promoting tumor growth, angiogenesis and formation of the myeloid derived suppressor cells.  Inhibition of the CSF-1R signaling pathway blocks the activation of tumor-associated macrophages, which are involved in suppressing immune responses against tumors.

In addition to the BTC trial, six sulfatinib clinical trials are underway in China and the United States, including two Phase III studies in neuroendocrine tumor patients (SANET-p and SANET-ep) and a Phase II study in thyroid cancer patients.

The SANET-p trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III pivotal registration trial to treat about 190 pathologically low or intermediate grade pancreatic NET patients in China whose disease has progressed, locally advanced or distant metastasized and for whom there is no effective therapy.  The primary endpoint is PFS, with secondary endpoints including ORR, DCR, duration of response, time to response and OS.  Additional details of the SANET-p study may be found at clinicaltrials.gov, using identifier NCT02589821.  The SANET-ep trial is similar to the SANET-p trial and is targeted at treating about 270 non-pancreatic NET patients in China.  Additional details of the SANET-ep study may be found at clinicaltrials.gov, using identifier NCT02588170.

Chi-Med is conducting an open-label Phase II clinical trial to evaluate the efficacy and safety of sulfatinib in about 50 patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer or medullary thyroid cancer in China.  The primary endpoint is ORR, with secondary endpoints including the safety and tolerability, DCR, time to response and PFS.  Additional details of this study may be found at clinicaltrials.gov, using identifier NCT02614495.

---

[1] A Ananthakrishnan et al; Epidemiology of Primary and Secondary Liver Cancers; Semin Intervent Radiol. 2006 Mar; 23(1): 47–63.

[2] JA Bridgewater et al; Biliary Tract Cancer: Epidemiology, Radiotherapy, and Molecular Profiling; Am Soc Clin Oncol Educ Book. 2016;35:e194-203.

About Chi-Med

Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products.  Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the “safe harbor” provisions of the U.S. Private Securities Litigation Reform Act of 1995.  These forward-looking statements reflect Chi-Med’s current expectations regarding future events, including its expectations for the clinical development of sulfatinib, plans to initiate clinical studies for sulfatinib, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, assumptions regarding enrollment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of drug candidate sulfatinib to meet the primary or secondary endpoint of a study, to obtain regulatory approval in different jurisdictions, to gain commercial acceptance after obtaining regulatory approval, the potential market of sulfatinib for a targeted indication and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.  For further discussion of these and other risks, see Chi-Med’s filings with the U.S. Securities and Exchange Commission and on AIM. Chi-Med undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise. 

Contacts

Investor Enquiries
Christian Hogg, CEO	+852 2121 8200
International Media Enquiries
Anthony Carlisle, Citigate Dewe Rogerson	+44 7973 611 888 (Mobile)	anthony.carlisle@cdrconsultancy.co.uk
U.S. Based Media Enquiries
Brad Miles, BMC Communications	+1 (917) 570 7340 (Mobile)	bmiles@bmccommunications.com
Susan Duffy, BMC Communications	+1 (917) 499 8887 (Mobile)	sduffy@bmccommunications.com
Investor Relations
Matt Beck, The Trout Group	+1 (917) 415 1750 (Mobile)	mbeck@troutgroup.com
David Dible, Citigate Dewe Rogerson	+44 7967 566 919 (Mobile)	david.dible@citigatedr.co.uk
Panmure Gordon (UK) Limited
Richard Gray / Andrew Potts	+44 (20) 7886 2500

 

London: Monday, March 21, 2016: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that Hutchison MediPharma Limited (“HMP”), its drug R&D subsidiary, has initiated SANET-p, a Phase III registration trial of sulfatinib (HMPL-012) in China in patients with pancreatic neuroendocrine tumors (“NETs”).  The first patient was dosed on March 18, 2016.

The protocol for SANET-p is similar to SANET-ep, a Phase III registration trial in patients with extra-pancreatic NETs.  SANET-p is a randomized, double-blind, placebo-controlled, multi-center Phase III sulfatinib registration study to treat patients with low or intermediate grade advanced NET whose disease has progressed, locally advanced or distant metastasized and for whom there is no effective therapy.  Patients are randomized at a 2:1 ratio to receive either 300 milligrams of sulfatinib orally once per day, or placebo, on an every 28-day treatment cycle.  The primary objective of this study is to evaluate the progression-free survival of sulfatinib as compared to that of placebo, with secondary endpoints including objective response rate (“ORR”), disease control rate, time to response, duration of response, overall survival, safety and tolerability.  Approximately 195 patients are expected to be enrolled in the SANET-p study from more than 20 centers across China, with top-line results expected in 2018.  Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02589821.

Sulfatinib is an oral drug candidate that selectively inhibits the tyrosine kinase activity associated with the vascular endothelial growth factor receptor (“VEGFR”) and fibroblast growth receptor (“FGFR”), two tyrosine kinase receptors associated with angiogenesis and tumor growth.  HMP believes that sulfatinib’s VEGFR/FGFR1 inhibition profile has strong potential in second-line thyroid cancer patients, particularly in China where there are few safe and effective treatment options for this patient population.

Including this trial, HMP is conducting five Phase II and Phase III clinical trials of sulfatinib in China and the U.S.

 

Ends

 

Contact

Chi-Med

International Media Enquiries

U.S. Based Media Enquiries

Investor Relations

Panmure Gordon (UK) Limited

 

Notes to Editors

Overview of sulfatinib clinical development

NETs arise from neuroendocrine cells and develop predominantly in the digestive or respiratory tracts but can also occur in many areas of the body.  Diagnosing NETs is difficult due to the small tumor size and diverse occurrence with patients showing varied or no symptoms.  As a result, it has been difficult to accurately estimate the number of NETs incidences per year.  There were approximately 19,000 new cases of NETs and a cumulative prevalence of approximately 144,000 cases in the U.S. in 2015, according to Frost and Sullivan.

In 2014, HMP completed the first-in-human Phase I clinical trial of sulfatinib in China; the detailed results were presented at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics in early November 2015 (www.chi-med.com/sulfatinib-ph1-eortc-2015/).  The Phase I clinical data indicates that sulfatinib has a superior ORR in NET patients.  An ORR of 44% was observed for sulfatinib in 18 evaluable patients, compared to less than 10% for sunitinib and everolimus, the two approved targeted therapies for pancreatic NET patients.  Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02133157.

In October 2014, HMP initiated a multi-center, single-arm, open-label Phase Ib/II study in broad spectrum NET patients (pancreatic, gastrointestinal, liver, lymph and lung, among others) in China to further evaluate the efficacy, safety, tolerability, and pharmacokinetic characteristics of sulfatinib.  This study completed enrolment of 81 patients in December 2015.  HMP expects to report top line results of this study during the course of 2016.  Additional details about this study may be found using identifier NCT02267967.

In addition to SANET-p, in December 2015 HMP initiated SANET-ep, a Phase III sulfatinib registration trial in China in patients with extra-pancreatic NETs (non-pancreatic).  SANET-ep is a randomized, double-blind, placebo-controlled, multi-center registration study to treat pathologically low or intermediate grade NET patients whose disease has progressed, locally advanced or distant metastasized and for whom there is no effective therapy.  Additional details about this study may be found using identifier NCT02588170.

A Phase I study in Caucasian patients also began in November 2015 in the U.S.  Once HMP has established the Phase II dose among Caucasian patients in this U.S. Phase I study, HMP expects to start a U.S. Phase II study in broad spectrum NET patients in the second half of 2016.  Additional details about this study may be found using identifier NCT02549937.

In addition to these NET studies, in March 2016 HMP initiated a Phase II study in China to evaluate the safety, pharmacokinetics and efficacy of sulfatinib in patients with both medullary and differentiated thyroid cancer.  Additional details about this study may be found using identifier NCT02614495.

 

About VEGFR and FGFR in cancer

At an advanced stage, tumors secrete large amounts of vascular endothelial growth factor (“VEGF”), a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor in order to provide greater blood flow, oxygen, and nutrients to fuel the rapid growth of the tumor.  Anti-angiogenesis drugs have demonstrated benefits in a wide variety of tumor types.  VEGF and other ligands can bind to VEGF receptors, which have been shown to play a role in angiogenesis.  Inhibition of the VEGF/VEGFR signaling pathway can act to stop the growth of the vasculature around the tumor and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly.

Fibroblast cell growth factor (“FGF”) also plays a key role in tumor angiogenesis.  Aberrant activation of the FGF/FGFR signaling pathway is shown to be associated with cancer progression by promoting growth, survival, migration and invasion of the tumor.  There is evidence that anti-VEGF therapy treatment could increase FGFR pathway activation, leading to drug resistance to anti-VEGF therapies.  It is believed that simultaneously targeting VEGFR and FGFR could be an attractive approach to improve clinical efficacy.

 

About HMP

HMP is a novel drug R&D company focusing on discovering, developing and commercializing innovative therapeutics in oncology and autoimmune diseases.  With a team of around 290 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.  HMP is a subsidiary of Chi-Med.  For more information, please visit: www.hmplglobal.com.

 

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products.  Its Innovation Platform focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This announcement contains forward-looking statements that reflect Chi-Med’s current expectations regarding future events, including its plans to initiate clinical studies for its drug candidates in the targeted indications, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, assumptions regarding enrolment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of a drug candidate to meet the primary or secondary endpoint of a study, the ability of a drug candidate to obtain regulatory approval in different jurisdictions, the ability of a drug candidate to gain commercial acceptance after obtaining regulatory approval and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.  Chi-Med undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise.

London: Wednesday, 2 March 2016: Hutchison China MediTech Limited (“Chi-Med”) (AIM: HCM) today announces that Hutchison MediPharma Limited (“HMP”), its drug R&D subsidiary, has initiated an open-label Phase II clinical trial to evaluate the efficacy and safety of sulfatinib (HMPL-012) in patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (“DTC”) or medullary thyroid cancer (“MTC”) in China. The first patient was dosed on 1 March 2016.

HMP plans to enroll approximately 50 DTC and MTC patients into this study, with approximately 25 patients in each tumor type. The primary objective is to evaluate the objective response rate (“ORR”), while secondary and exploratory objectives include the evaluation of safety and tolerability, other efficacy parameters, pharmacokinetics, and tumor biomarkers. The study employs a two-stage design in which 15 subjects of each tumor type will be enrolled in the first stage. An additional 10 subjects in each tumor type will be enrolled after efficacy assessment in the second stage. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02614495.

Sulfatinib is an oral drug candidate that selectively inhibits the tyrosine kinase activity associated with the vascular endothelial growth factor receptor (“VEGFR”) and fibroblast growth receptor (“FGFR”), two tyrosine kinase receptors associated with angiogenesis and tumor growth. HMP believes that sulfatinib’s VEGFR/FGFR1 inhibition profile has strong potential in second-line thyroid cancer patients, particularly in China where there are few safe and effective treatment options for this patient population.

In addition to the thyroid cancer trial, HMP is conducting or in the process of initiating four clinical trials in neuroendocrine tumors (“NETs”).

Ends

 

Enquiries

 

Christian Hogg, CEO

 

Richard Gray
Andrew Potts

 

 

Notes to Editors

 

About thyroid cancer

Thyroid cancer is the most commonly diagnosed endocrine malignancy. Global incidence rates have increased sharply and continuously over the past few decades. According to the National Cancer Institute (“NCI”), in the U.S., incidence rates of thyroid cancer have increased by an average of 5% each year over the last 10 years. Further, an article published in Cancer Research estimates that it could become the fourth most commonly diagnosed cancer by 2030. In China, thyroid cancer is now the fastest growing tumor type and accounted for approximately 2% of all new cancer cases reported in 2015, according to the National Central Cancer Registry of China (“NCCRC”).

This rise in incidence has been most dramatic in women. According to through the NCCRC, 67,900 new cases were reported in women compared to just 22,200 in men in China in 2015. Thyroid cancer now represents the most frequently diagnosed cancer in Chinese women under the age of 30. In the U.S., incidence rates of thyroid cancer are three-fold higher in women than in men, according to the NCI.

 

Overview of sulfatinib clinical development in NETs

NETs arise from neuroendocrine cells and develop predominantly in the digestive or respiratory tracts but can also occur in many areas of the body. Diagnosing NETs is difficult due to the small tumor size and diverse occurrence with patients showing varied or no symptoms. As a result, it has been difficult to accurately estimate the number of NETs incidences per year. There were approximately 19,000 new cases of NETs and a cumulative prevalence of approximately 144,000 cases in the U.S. in 2015, according to Frost and Sullivan.

In 2014, HMP completed the first-in-human Phase I clinical trial of sulfatinib in China; the detailed results were presented at the American Association for Cancer Research-National Cancer Institute-European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics in early November 2015 (www.chi-med.com/sulfatinib-ph1-eortc-2015/). The Phase I clinical data indicates that sulfatinib has a superior ORR in NET patients. An ORR of 44% was observed for sulfatinib in 18 evaluable patients, compared to less than 10% for sunitinib and everolimus, the two approved targeted therapies for pancreatic NET patients. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02133157.

In October 2014, HMP initiated a multi-center, single-arm, open-label Phase Ib/II study in broad spectrum NET patients (pancreatic, gastrointestinal, liver, lymph and lung, among others) in China to further evaluate the efficacy, safety, tolerability, and pharmacokinetic characteristics of sulfatinib. This study completed enrolment of 81 patients in December 2015. HMP expects to report top line results of this study during the course of 2016. Additional details about this study may be found using identifier NCT02267967.

In December 2015, HMP initiated SANET-ep, a Phase III sulfatinib registration trial in China in patients with extra-pancreatic NETs (non-pancreatic). SANET-ep is a randomized, double-blind, placebo-controlled, multi-center registration study to treat pathologically low or intermediate grade NET patients whose disease has progressed, locally advanced or distant metastasized and for whom there is no effective therapy. Additional details about this study may be found using identifier NCT02588170.

In the first quarter 2016, HMP intends to initiate a second sulfatinib Phase III registration trial, SANET-p, in pancreatic NET patients. SANET-p employs a similar treatment regimen and has primary and secondary endpoints similar to those for SANET-ep trial. HMP plans to enroll about 195 patients in SANET-p. Additional details about this study may be found using identifier NCT02589821.

A Phase I study in Caucasian patients also began in November 2015 in the U.S. Once HMP has established the Phase II dose among Caucasian patients in this U.S. Phase I study, HMP expects to start a U.S. Phase II study in broad spectrum NET patients in the second half of 2016. Additional details about this study may be found using identifier NCT02549937.

 

About VEGFR and FGFR in cancer

At an advanced stage, tumors secrete large amounts of vascular endothelial growth factor (“VEGF”), a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor in order to provide greater blood flow, oxygen, and nutrients to fuel the rapid growth of the tumor. Anti-angiogenesis drugs have demonstrated benefits in a wide variety of tumor types. VEGF and other ligands can bind to VEGF receptors, which have been shown to play a role in angiogenesis. Inhibition of the VEGF/VEGFR signaling pathway can act to stop the growth of the vasculature around the tumor and thereby starve the tumor of the nutrients and oxygen it needs to grow rapidly.

Fibroblast cell growth factor (“FGF”) also plays a key role in tumor angiogenesis. Aberrant activation of the FGF/FGFR signaling pathway is shown to be associated with cancer progression by promoting growth, survival, migration and invasion of the tumor. There is evidence that anti-VEGF therapy treatment could increase FGFR pathway activation, leading to drug resistance to anti-VEGF therapies. It is believed that simultaneously targeting VEGFR and FGFR could be an attractive approach to improve clinical efficacy.

 

About HMP

HMP is a novel drug R&D company focusing on discovering, developing and commercializing innovative therapeutics in oncology and autoimmune diseases. With a team of around 290 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. HMP is a subsidiary of Chi-Med. For more information, please visit: www.hmplglobal.com.

 

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products. Its Innovation Platform focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This announcement contains forward-looking statements that reflect Chi-Med’s current expectations regarding future events, including its plans to initiate clinical studies for its drug candidates in the targeted indications, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrolment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of a drug candidate to meet the primary or secondary endpoint of a study, the ability of a drug candidate to obtain regulatory approval in different jurisdictions, the ability of a drug candidate to gain commercial acceptance after obtaining regulatory approval and the sufficiency of funding. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Chi-Med undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise.

London: Friday, 18 December 2015: Hutchison China MediTech Limited (“Chi-Med”) (AIM: HCM) today announces that Hutchison MediPharma Limited (“HMP”), its drug R&D subsidiary, has initiated SANET-ep, a Phase III sulfatinib (HMPL-012) registration trial in China in patients with extra-pancreatic neuroendocrine tumours (“NETs”), which are all non-pancreatic NETs, including, for example, NETs originating in the lymph, lung and across the gastrointestinal tract.  Preparations and site selection had begun in the middle of this year and the first patient was dosed on 17 December 2015.

SANET-ep is a randomised, double-blind, placebo-controlled, multi-centre Phase III sulfatinib registration study to treat pathologically low or intermediate grade NET patients whose disease has progressed, locally advanced or distant metastasised and for whom there is no effective therapy.  Patients will be randomised at a 2:1 ratio to receive either 300 milligrams of sulfatinib orally once per day, or placebo, on every 28-day treatment cycle.  The primary objective of this study is to evaluate the progression-free survival of sulfatinib as compared to that of placebo, with secondary endpoints including objective response rate (“ORR”), disease control rate, time to response, duration of response, overall survival, safety and tolerability.  Approximately 270 patients will be enrolled in the SANET-ep study from more than 20 centres across China, with top-line results expected in 2018.

Additionally, the second Phase III sulfatinib registration trial, SANET-p, in pancreatic NET patients, is expected to be initiated imminently in China.  SANET-p employs a similar treatment regimen and has primary and secondary endpoints similar to those for SANET-ep trial.  Approximately 195 patients will be enrolled in SANET-p and is expected to start by the end of 2015, with top-line results expected in 2017.

Sulfatinib is an oral drug candidate that demonstrates dual inhibition of the tyrosine kinase activity associated with vascular endothelial growth factor receptor (“VEGFR”) and fibroblast growth factor receptor (“FGFR”) 1, a receptor kinase which also plays a role in tumour angiogenesis.  In 2014, HMP completed the first-in-human Phase I clinical trial of sulfatinib in China; the detailed results were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in early November 2015 (www.chi‑med.com/sulfatinib-ph1-eortc-2015/).  The Phase I clinical data indicates that sulfatinib has the highest ORR reported to date in NET patients.  An ORR of 44% was observed for sulfatinib in 18 evaluable patients, compared to less than 10% for sunitinib and everolimus, the two approved targeted therapies for pancreatic NET patients.

In October 2014, HMP initiated a multi-centre, single-arm, open-label Phase Ib/II study in NET patients in China to further evaluate the efficacy, safety, tolerability and pharmacokinetic characteristics of sulfatinib.  This study, projected to enrol approximately 80 patients, is near to completion of patient enrolment.

Furthermore, the Phase I and Phase Ib/II studies in China provide a guide for the selection of the recommended starting dose for the Phase I study in patients with advanced solid tumours in the United States, which had the first patient enrolled in early November 2015.

In addition to these four NET studies, HMP also plans to initiate a Phase Ib study in China to evaluate the safety, pharmacokinetics and efficacy of sulfatinib in patients with both medullary and differentiated thyroid cancer by the end of 2015.

 

Ends

 

Enquiries

Christian Hogg, CEO

 

Richard Gray
Andrew Potts

 

 

Notes to Editors

About neuroendocrine tumours

Neuroendocrine tumours arise from neuroendocrine cells and develop predominantly in the digestive or respiratory tracts but can also occur in other organs of the body.  Diagnosis of neuroendocrine tumours is difficult due to the small tumour size and diverse origination with patients showing varied or no symptoms.  It is estimated that there are approximately 19,000 new cases of neuroendocrine tumours per year and a cumulative prevalence of approximately 141,000 cases in the United States in 2014.

Neuroendocrine tumours can be classified according to tumour origin, as pancreatic NET representing less than 10% of the total NET patients, and extra-pancreatic NET comprising all other non-pancreatic NETs including lung, lymph and gastrointestinal tract NETs.  To date, treatment options for NET patients are limited; sunitinib and everolimus are the only two approved targeted-therapies for pancreatic NET, while there is no such a choice for extra-pancreatic NET patients.

 

About VEGFR and FGFR in cancer

At an advanced stage, tumours secrete large amounts of vascular endothelial growth factor (“VEGF”), a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumour in order to provide greater blood flow, oxygen, and nutrients to fuel the rapid growth of the tumour.  Anti-angiogenesis drugs have demonstrated benefits in a wide variety of tumour types.  VEGF and other ligands can bind to VEGF receptors, which have been shown to play a role in angiogenesis.  Inhibition of the VEGF/VEGFR signalling pathway can act to stop the growth of the vasculature around the tumour and thereby starve the tumour of the nutrients and oxygen it needs to grow rapidly.

Fibroblast cell growth factor (“FGF”) also plays a key role in tumour angiogenesis.  Aberrant activation of the FGF/FGFR signalling pathway is shown to be associated with cancer progression by promoting growth, survival, migration and invasion of the tumour.  There is evidence that anti-VEGF therapy treatment could increase FGFR pathway activation, leading to drug resistance to anti-VEGF therapies.  It is believed that simultaneously targeting VEGFR and FGFR could be an attractive approach to improve clinical efficacy.

 

About HMP

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 over 280 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.  HMP is a subsidiary of Chi-Med.  For more information, please visit: www.hmplglobal.com.

 

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products.  Its Innovation Platform focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

 

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This announcement contains forward-looking statements that reflect Chi-Med’s current expectations regarding future events, including its plans to initiate clinical studies for its drug candidates in the targeted indications, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, assumptions regarding enrolment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of a drug candidate to meet the primary or secondary endpoint of a study, the ability of a drug candidate to obtain regulatory approval in different jurisdictions, the ability of a drug candidate to gain commercial acceptance after obtaining regulatory approval and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.  Chi-Med undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise.

Abstract (download poster for full details):

Authors: Jian-Ming Xu, Lin Shen, Yan Wang, Yu-ling Chen, Ru Jia, Jian Wang, Ke Li, Yang Sai, Jing Li, Chuan Qi, Hua Ye, Su Weiguo

Background: Sulfatinib is a highly selective oral small molecule inhibitor targeting both vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR).  A phase I dose-escalation study was carried out to determine sulfatinib maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), pharmacokinetic (PK) profiles, and preliminary antitumor activity in patients with advanced solid tumours.

Methods: Sulfatinib was administered orally in 28-day treatment cycles until disease progression or unacceptable toxicity.  The study utilized 3+3 dose escalation method, with ascending dose cohorts from 50mg to 350mg daily.  During the study, a milled formulation was developed to reduce the inter-patient PK variations and optimize drug absorption.  The milled formulation was used in 200mg once daily (QD) to 350mg QD dose cohorts.

Results: As of July 6, 2015, a total of 77 patients had been enrolled.  Forty‑three of the 77 patients received original formulation in dose cohorts from 50mg to 300mg daily.  The data of patients treated with original formulation dosing from 50 to 300mg once daily, or 125mg and 150mg twice daily were reported in ASCO 2012(#3040).  Thirty-four of the 77 patients received milled formulation.  Among the 34 patients, 23 were enrolled in the dose-escalation phase, receiving sulfatinib 200mg to 350mg QD whereas 11 patients were enrolled in the dose-expansion phase receiving sulfatinib 300mg or 350 mg QD.  Among the 34 patients, there were 24 male patients (70.6%) and 10 female patients (29.4%).  The median age was 55.97 (23.35-73.17) years.  The most common adverse events of 34 patients were hypertension, proteinuria, diarrhoea, elevated AST/ALT and decreased blood albumin, mostly grade1/2.  One DLT (grade 3 ALT/AST increase) was observed in the 200 mg QD dose group.  MTD was not reached up to 350mg QD.  Among the 34 subjects treated with milled formulation, 22 subjects were diagnosed with neuroendocrine tumours (NETs).  Eight NET patients (5 in 300mg QD and 3 in 350mg QD cohort) had confirmed partial response (PR) with median duration of response (DoR) of 13.8 months.  The tumour origins of the 8 NET patients include pancreas (3 patients), duodenum (1 patient), rectum (1 patient), thymus (1 patient) and unknown origin (2 patients).  Objective response rate among the 18 efficacy evaluable NET patients was 44.4% and disease control rate was 100%.  Sulfatinib half-life (t_1/2) in plasma averaged 14-20 hours at the test dose levels, which supported sulfatinib QD dosing frequency.  Following QD multiple dosing, sulfatinib achieved steady state on Day 14.  The drug exposure increased when the dose increased from 200 mg to 300 mg, and then plateaued from 300 mg to 350 mg. Based on the clinical safety, efficacy, and PK data, the recommended Phase II dose is determined to be 300 mg QD.

Conclusions: Sulfatinib was well tolerated with an acceptable safety profile.  Promising anti-tumour activity was observed in NET patients.  Further clinical studies with sulfatinib are warranted.

London: Friday, 6 November 2015: Hutchison China MediTech Limited (“Chi-Med”) (AIM: HCM) today announces that Hutchison MediPharma Limited (“HMP”), its drug R&D subsidiary, has initiated the Phase I clinical trial of sulfatinib (HMPL-012) in the United States.  Its U.S. Investigational New Drug application was submitted and cleared earlier this year and the first patient was dosed on 4 November 2015.  HMP is also planning to initiate two Phase III registration studies for the treatment of neuroendocrine tumours (“NET”) and a Phase Ib study for the treatment of thyroid cancer with sulfatinib in China by the end of 2015.

This Phase I dose escalation study is to assess the safety and tolerability of sulfatinib in U.S. patients with advanced solid tumours.  A U.S. Phase II study in NET is expected to be initiated based on the conclusion of this Phase I dose escalation study.

Sulfatinib is an oral drug candidate that selectively inhibits the tyrosine kinase activity associated with the vascular endothelial growth factor receptor (“VEGFR”) and fibroblast growth receptor (“FGFR”), a receptor for a protein which also plays a role in tumour growth.  In a Phase I clinical trial in China focusing on NET patients, sulfatinib’s objective response rate among the 18 efficacy-evaluable NET patients was 44.4%.  By comparison, sunitinib and everolimus, the two approved single agent therapies for pancreatic NET, achieved objective response rates of less than 10% in their pivotal clinical trials.  Furthermore, NET responses to sulfatinib have been observed to improve gradually with time.  Results of the Phase I trial in China will be reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November 2015 and will be made available at www.chi‑med.com/news/.

Sulfatinib is the first oncology candidate that HMP has taken through proof-of-concept in China and expanded to a U.S. clinical study without a partner.

 

Ends

 

Enquiries

Christian Hogg, CEO

 

Richard Gray
Andrew Potts

 

 

Notes to Editors

Overview of sulfatinib clinical development

In addition to the U.S. Phase I clinical trial, HMP is conducting or in the process of initiating four clinical trials in China.

NET

In October 2014, HMP initiated a multi-centre, single-arm, open-label Phase Ib/II study in broad spectrum NET patients (pancreatic, gastrointestinal, liver, lymph and lung, among others) in China to further evaluate the efficacy, safety, tolerability, and pharmacokinetic characteristics of sulfatinib.  This study, projected to enrol approximately 80 patients, is near to completion of patient enrolment.  Results to date of this open-label Phase Ib study appear generally in line with the positive results from the Phase I study.

Encouraged by these results, HMP now plans to start two Phase III registration studies in China by the end of 2015, one in pancreatic NET patients and a second in advanced carcinoid (non-pancreatic) NET patients.

Thyroid cancer

HMP plans to initiate a Phase Ib study in China to evaluate the safety, pharmacokinetics and efficacy of sulfatinib in patients with both medullary and differentiated thyroid cancer by the end of 2015.  Sulfatinib’s VEGFR/FGFR1 inhibition profile is believed to have strong potential in second-line thyroid cancer patients, particularly in China where there are few safe and effective treatment options for this patient population.  HMP plans to enrol approximately 50 patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer or medullary thyroid cancer into this study, with approximately 25 patients in each tumour type.

 

About NET

NET arises from neuroendocrine cells and develop predominantly in the digestive or respiratory tracts but can also occur in many areas of the body.  Diagnosing NET is difficult due to the small tumour size and diverse occurrence with patients showing varied or no symptoms.  As a result, it has been difficult to accurately estimate the number of NET incidences per year.  There were approximately 19,000 new cases of NET and a cumulative prevalence of approximately 141,000 cases in the United States in 2014.

 

About HMP

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 250 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.  HMP is a subsidiary of Chi-Med.  For more information, please visit: www.hmplglobal.com.

 

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products.  Its Innovation Platform focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This announcement contains forward-looking statements that reflect Chi-Med’s current expectations regarding future events, including its plans to initiate clinical studies for its drug candidates in the targeted indications, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies.  Forward-looking statements involve risks and uncertainties.  Such risks and uncertainties include, among other things, assumptions regarding enrolment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of a drug candidate to meet the primary or secondary endpoint of a study, the ability of a drug candidate to obtain regulatory approval in different jurisdictions, the ability of a drug candidate to gain commercial acceptance after obtaining regulatory approval and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof.  Chi-Med undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise.

 Press Release

London: Friday, 30 October 2015: Hutchison China MediTech Limited (“Chi‑Med”) (AIM: HCM) today announces that Hutchison MediPharma Limited (“HMP”), its drug R&D subsidiary, will present further scientific data on sulfatinib (HMPL‑012), fruquintinib (HMPL‑013) and savolitinib (AZD6094, HMPL‑504) at the International Conference on Molecular Targets and Cancer Therapeutics, which will be held in Boston, Massachusetts, USA from 5 to 9 November 2015.  Sulfatinib, fruquintinib and savolitinib were all discovered by HMP and are currently being evaluated in clinical trials for the treatment of various cancers.

Sulfatinib is an oral drug candidate that selectively inhibits the tyrosine kinase activity associated with the vascular endothelial growth factor receptor (“VEGFR”) and fibroblast growth receptor (“FGFR”), a receptor for a protein which also plays a role in tumour growth.  HMP will present clinical data from its Phase I trial in China, focusing on neuroendocrine tumour (“NET”) patients.  In this study, sulfatinib’s objective response rate among the 18 efficacy-evaluable NET patients was 44.4% and disease control rate was 100%.  By comparison, sunitinib and everolimus, the two approved single agent therapies for neuroendocrine tumours, achieve objective response rates of less than 10% in their pivotal clinical trials.  Furthermore, neuroendocrine tumour responses to sulfatinib have been observed to improve gradually with time.

Savolitinib is an inhibitor of the c-Met receptor tyrosine kinase, an enzyme which has been shown to function abnormally in many types of solid tumours, and fruquintinib is a highly selective inhibitor of VEGFR1, 2 and 3.  In clear cell renal cell carcinoma (“ccRCC”), c-Met activation has emerged as one of the mechanisms for resistance to anti-VEGF/VEGFR therapies, implying that inhibition of the c-Met and VEGFR pathways in a combination therapy could produce additional clinical benefit.  HMP will present data from a preclinical study to assess the effect of savolitinib and fruquintinib combined in ccRCC xenograft models.  In this study, while single-agent treatment at clinically relevant doses only exhibited mild to moderate tumour growth inhibition, a significantly increased anti-tumour effect was observed for the group receiving combination therapy.

Preclinical data will also be presented regarding savolitinib in non-small cell lung cancer (“NSCLC”) and mechanisms of acquired savolitinib resistance.

The following posters will be made available at www.chi‑med.com/news/ after they are presented at the conference:

 

1st Presentation Title:	First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumours
Authors:	Jian-Ming Xu, et al.
Session:	Poster Session A – Angiogenesis and Antiangiogenesis Agents
Date & Time:	Friday 6 November 2015, 12:15 PM – 3:15 PM

 

2nd Presentation Title:	Synergistic effect of c-Met inhibitor Savolitinib in combination with a VEGFR inhibitor Fruquintinib in clear cell renal cell carcinoma xenograft models
Authors:	Yongxin Ren, et al.
Session:	Poster Session B –Therapeutic Agents: Small Molecule Kinase Inhibitors
Date & Time:	Saturday 7 November 2015, 12:30 PM – 3:30 PM

 

3rd Presentation Title:	Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signalling
Authors:	Ryan Henry, et al.
Session:	Late-Breaking Poster Session – Drug Resistance and Modifiers
Date & Time:	Sunday 8 November 2015, 12:30 PM – 3:30 PM

 

Hosted by the American Association for Cancer Research (“AACR”), the National Cancer Institute (“NCI”), and the European Organisation for Research and Treatment of Cancer (“EORTC”), the 2015 Molecular Targets and Cancer Therapeutics conference will bring together an estimated 3,000 academics, scientists, and pharmaceutical industry representatives from across the globe to discuss innovations in drug development, target selection, and the impact of new discoveries in molecular biology.

 

Ends

 

Enquiries

Chi-Med
Telephone:      +852 2121 8200
Christian Hogg, CEO

 

Panmure Gordon (UK) Limited
Telephone:      +44 20 7886 2500
Richard Gray
Andrew Potts

 

Citigate Dewe Rogerson
Telephone:      +44 20 7638 9571
Anthony Carlisle, Mobile: +44 7973 611 888
David Dible, Mobile: +44 7967 566 919

 

Notes to Editors

Abstracts

Title:    First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumours

Authors: Jian-Ming Xu, Lin Shen, Yan Wang, Yu-ling Chen, Ru Jia, Jian Wang, Ke Li, Yang Sai, Jing Li, Chuan Qi, Hua Ye, Su Weiguo

Background: Sulfatinib is a highly selective oral small molecule inhibitor targeting both vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR).  A phase I dose-escalation study was carried out to determine sulfatinib maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), pharmacokinetic (PK) profiles, and preliminary antitumor activity in patients with advanced solid tumours.

Methods: Sulfatinib was administered orally in 28-day treatment cycles until disease progression or unacceptable toxicity.  The study utilized 3+3 dose escalation method, with ascending dose cohorts from 50mg to 350mg daily.  During the study, a milled formulation was developed to reduce the inter-patient PK variations and optimize drug absorption.  The milled formulation was used in 200mg once daily (QD) to 350mg QD dose cohorts.

Results: As of July 6, 2015, a total of 77 patients had been enrolled.  Forty‑three of the 77 patients received original formulation in dose cohorts from 50mg to 300mg daily.  The data of patients treated with original formulation dosing from 50 to 300mg once daily, or 125mg and 150mg twice daily were reported in ASCO 2012(#3040).  Thirty-four of the 77 patients received milled formulation.  Among the 34 patients, 23 were enrolled in the dose-escalation phase, receiving sulfatinib 200mg to 350mg QD whereas 11 patients were enrolled in the dose-expansion phase receiving sulfatinib 300mg or 350 mg QD.  Among the 34 patients, there were 24 male patients (70.6%) and 10 female patients (29.4%).  The median age was 55.97 (23.35-73.17) years.  The most common adverse events of 34 patients were hypertension, proteinuria, diarrhoea, elevated AST/ALT and decreased blood albumin, mostly grade1/2.  One DLT (grade 3 ALT/AST increase) was observed in the 200 mg QD dose group.  MTD was not reached up to 350mg QD.  Among the 34 subjects treated with milled formulation, 22 subjects were diagnosed with neuroendocrine tumours (NETs).  Eight NET patients (5 in 300mg QD and 3 in 350mg QD cohort) had confirmed partial response (PR) with median duration of response (DoR) of 13.8 months.  The tumour origins of the 8 NET patients include pancreas (3 patients), duodenum (1 patient), rectum (1 patient), thymus (1 patient) and unknown origin (2 patients).  Objective response rate among the 18 efficacy evaluable NET patients was 44.4% and disease control rate was 100%.  Sulfatinib half-life (t_1/2) in plasma averaged 14-20 hours at the test dose levels, which supported sulfatinib QD dosing frequency.  Following QD multiple dosing, sulfatinib achieved steady state on Day 14.  The drug exposure increased when the dose increased from 200 mg to 300 mg, and then plateaued from 300 mg to 350 mg. Based on the clinical safety, efficacy, and PK data, the recommended Phase II dose is determined to be 300 mg QD.

Conclusions: Sulfatinib was well tolerated with an acceptable safety profile.  Promising anti-tumour activity was observed in NET patients.  Further clinical studies with sulfatinib are warranted.

 

Title:   Synergistic effect of c-Met inhibitor Savolitinib in combination with a VEGFR inhibitor Fruquintinib in clear cell renal cell carcinoma xenograft models

Authors: Yongxin Ren, Shiming Fan, Yunxin Chen, Renxiang Tang, Wei Zhang, Jianxing Tang, Linfang Wang, Dongxia Shi, Hongbo Chen, Min Cheng, Weiguo Qing, Weiguo Su

Renal cell carcinoma (RCC) is the most common type of kidney tumour in human.  Approximately 80~85% of RCC is clear cell renal cell carcinoma (ccRCC).  Although VEGF/VEGFR targeted therapies bring significant advances in the treatment of RCC, ultimate resistance occurs in most cases following a transient period of clinical benefit.  The hepatocyte growth factor (HGF) receptor c-Met activation emerges as one of the mechanisms for resistance to anti-VEGF/VEGFR therapies in ccRCC, implying that a combinational inhibition of c-Met and VEGFR pathways may induce a synergistic anti-tumour effect and could produce additional clinical benefit. The aim of this study was to assess the effect of a combination strategy targeting the VEGFR and c-MET pathways in ccRCC xenograft models.

Savolitinib (AZD6094, HMPL‑504) is a highly selective inhibitor against c-Met.  Fruquintinib (HMPL-013) strongly inhibits VEGFR1, 2 and 3.  Both of them were discovered by HMP and are currently being evaluated in clinical trials for the treatment of various cancers.  Several subcutaneous xenograft models were established in nude mice with human ccRCC cell lines or patient derived tumours (PDX) to investigate the anti-tumour effect of combination of savolitinib with fruquintinib.  Treatment with savolitinib or fruquintinib at clinically relevant dose only exhibited mild to moderate tumour growth inhibition as a single agent in all of tested models, but significantly increased anti-tumour effect was observed in all of tested models for the combination group.  It seemed that the enhanced anti-tumour effect was associated with c-Met inhibition.  In a ccRCC PDX model KIN1T1342, the increased anti-tumour effect was correlated with dose increment of savolitinib.  Immunohistochemistry (IHC) analysis revealed that combination treatment produced stronger inhibition on tumour proliferation marker Ki67 and angiogenesis marker CD31, compared to either savolitinib or fruquintinib alone, indicating that the observed synergistic effect might be attributed to the dual inhibition on tumour signalling and tumour microenvironment.  C-Met expression was observed in all tested models, and treatment with savolitinib effectively suppressed phospho-MET.

To evaluate c-Met expression in Chinese ccRCC patients, Formalin-Fixed and Paraffin-Embedded (FFPE) tumour sections were collected from sixty-two treatment-naive patients during surgical resection.  Positive c-Met expression was found in 69% (43/62) of ccRCC samples under IHC staining.

Overall our data demonstrated that c-Met was widely expressed in Chinese ccRCC patients and provided a rationale to test the combined HGF/c-Met and VEGF/VEGFR pathway blockade in the treatment of ccRCC in the clinical trials.

 

Title:   Acquired resistance to the cMET inhibitor savolitinib in lung cancer models through EGFR/mTOR/MYC deregulation and adoption of PIM signalling

Authors: Ryan E. Henry, Evan R. Barry, Brendon Ladd, Aleksandra Markovets, Garry J. Beran, Yongxin Ren, Feng Zhou, Lillian Castriotta, Ammar Adam, Weiguo Qing, Weiguo Su, Edwin Clark, Celina M. D’Cruz, Alwin Schuller.

Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments.  Aberrant receptor tyrosine kinase (RTK) signalling is a well-documented driver of disease onset and progression in multiple cancer types, including NSCLC, where the cMET RTK contributes to tumour progression, maintenance and resistance to targeted therapies.  Here, we explore the therapeutic potential of the potent and selective cMET inhibitor savolitinib (volitinib, AZD6094, HMPL‑504) in NSCLC and begin to elucidate mechanisms of acquired savolitinib resistance in preclinical models.  Using in vitro proliferation assays and immunoblot analysis, we determine that savolitinib rapidly inhibits cMET auto-phosphorylation/activation and reduces the viability of NSCLC cell lines NCI-H1993 and EBC-1 with a GI₅₀ of 4.20 nM and 2.14 nM, respectively.  In vivo, once daily treatment of NCI-H1993 xenografts with 3.0 mg/kg savolitinib significantly slows tumour growth, whereas treatment of EBC-1 xenografts with 30.0 mg/kg results in tumour stasis.  Importantly, we observe tumour regressions in a patient-derived xenograft model of a NSCLC lymph node metastasis, HLXF‑036LN, dosed with savolitinib 50.0 mg/kg once daily.  Pharmacodynamic analysis of in vitro and in vivo models shows that savolitinib sensitivity correlates with blockade of PI3K/AKT and MAPK signalling, and interestingly, with cMYC (MYC) protein down-regulation.  To elucidate mechanisms of acquired resistance in NSCLC, we generated savolitinib resistance in vitro using the NCI‑H1993 and EBC-1 cell lines and further sub-cloned resistant NCI‑H1993 cells to study the heterogeneity of resistance mechanisms.  Using small-molecule screening, phospho-protein arrays and interrogation of signalling pathway activity by immunoblot, we identify 1) deregulated mTORC1/2 signalling and 2) the uncoupling of MYC expression from cMET activation as commonly contributing to resistance in all clones tested.  RNA interference (siRNA) and MYC over-expression experiments confirm the novel finding that sustained MYC expression can partially drive resistance to a tyrosine kinase inhibitor such as savolitinib.  Additionally, we identify clone-specific resistance mechanisms arising via a previously-described switch to EGFR dependence or by our novel finding of a de novo requirement for PIM signalling.  Taken together, this work demonstrates the preclinical efficacy of savolitinib in NSCLC and provides an initial characterization of potential resistance mechanisms, identifying core resistance targets and clone-specific vulnerabilities that could be exploited to counter acquired savolitinib resistance that may emerge in the clinic.

 

About sulfatinib

Sulfatinib is an oral drug candidate that selectively inhibits the tyrosine kinase activity associated with VEGFR and FGFR.  Angiogenesis is an important mechanism in tumour pathogenesis, and inhibition of VEGF-mediated angiogenesis has been important in the treatment of a variety of cancers.  FGFR is a receptor for a protein which also plays a role in tumour growth.  HMP is conducting, or in the process of initiating, two Phase III and two Phase Ib clinical trials in China, and one Phase I clinical trial in the United States.  These trials are intended to assess the effectiveness of sulfatinib for the treatment of neuroendocrine cancer and thyroid cancer patients.

 

About fruquintinib

Fruquintinib is designed as a highly selective and potent oral inhibitor of VEGFR, namely VEGFR1, VEGFR2, and VEGFR3.  In March and September 2015, Chi-Med announced that the first proof-of-concept studies of fruquintinib in China in patients with third-line metastatic colorectal cancer and non-small cell lung cancer clearly met their primary endpoints of progression free survival by demonstrating superiority compared with placebo.  Fruquintinib was well tolerated in both studies, showing no major unexpected safety issues.  HMP is conducting or in the process of initiating two Phase III clinical trials in these indications.  HMP is also conducting a Phase Ib dose-finding study of fruquintinib, in combination with paclitaxel, in second line gastric cancer patients in China.

In October 2013, HMP entered into a licensing, co-development and commercialisation agreement with Eli Lilly for fruquintinib.

 

About savolitinib

Savolitinib is a potential global first-in-class inhibitor of c-Met, receptor tyrosine kinase, an enzyme which exhibits aberrant behaviour (e.g. gene amplification, over-expression and mutation) in many types of solid tumours.  Savolitinib was developed as a potent and highly selective oral c-Met inhibitor that was designed to address renal toxicity, the primary issue that has to-date prevented other selective c-Met inhibitors from gaining regulatory approval.  In Phase I/Ib clinical studies in Australia and China, savolitinib has shown promising signs of clinical efficacy, causing tumour size reduction, in c-Met aberrant patients in papillary renal cell carcinoma, non-small cell lung cancer, colorectal cancer and gastric cancer.

Currently, HMP and AstraZeneca AB, its partner on savolitinib, are conducting nine clinical studies of savolitinib monotherapy treatment as well as savolitinib in combination treatments with other tyrosine kinase inhibitors and chemotherapy in kidney, lung and gastric cancers.  Furthermore, by the end of 2015, HMP and AstraZeneca AB expect to initiate three further proof-of-concept studies for savolitinib, two of which will involve combinations with immunotherapies.

 

About Chi-Med

Chi-Med is a China-based, globally-focused healthcare group which researches, develops, manufactures and sells pharmaceuticals and health-related consumer products.  Its Innovation Platform focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market.  Its Commercial Platform manufactures, markets and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001).  For more information, please visit: www.chi-med.com.

 

Forward-Looking Statements

This announcement contains forward-looking statements that reflect Chi-Med’s current expectations regarding future events, including its plans to initiate clinical studies for its drug candidates in the targeted indications, its expectations as to whether such studies would meet their primary or secondary endpoints, and its expectations as to the timing of the completion and the release of results from such studies. Forward-looking statements involve risks and uncertainties. Such risks and uncertainties include, among other things, assumptions regarding enrolment rates, timing and availability of subjects meeting a study’s inclusion and exclusion criteria, changes to clinical protocols or regulatory requirements, unexpected adverse events or safety issues, the ability of a drug candidate to meet the primary or secondary endpoint of a study, the ability of a drug candidate to obtain regulatory approval in different jurisdictions, the ability of a drug candidate to gain commercial acceptance after obtaining regulatory approval and the sufficiency of funding.  Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Chi-Med undertakes no obligation to update or revise the information contained in this announcement, whether as a result of new information, future events or circumstances or otherwise.

London: Friday, 30 April 2010: Hutchison MediPharma Limited (“Hutchison MediPharma”), the wholly-owned drug R&D subsidiary of Chi-Med, today announces that it has initiated the first-in-human Phase I clinical trial of its anti-cancer drug candidate, Sulfatinib, after it received approval from the State Food and Drug Administration (“SFDA”) in China.  The investigational new drug application (“IND”) was reviewed through SFDA’s Green Channel expedited application process.  The first patients were dosed on 28 April 2010.

Sulfatinib (HMPL-012) is a novel small molecule that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factors (VEGFs) and fibroblast growth factor (FGF) receptors.  Pre-clinical data shows that this compound is a potent suppressor of angiogenesis, an established approach in anti-cancer treatment.  It also indicated that it is generally well tolerated in animals.  Sulfatinib was discovered and developed internally by Hutchison MediPharma.

The Phase I clinical study is being conducted in China.  The trial is an open-label, dose-escalation study.  The primary objective of the trial is to estimate the maximum tolerated dose (MTD) and assess the safety and tolerability in patients with advanced solid tumours.  The secondary objectives include the assessment of single and multiple dose pharmacokinetics and the evaluation of Sulfatinib’s antitumor activity.