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.
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