London: Friday, April 28, 2017: For information purposes, Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) hereby notifies the market that as at April 28, 2017, the issued share capital of Chi-Med consisted of 60,735,104 ordinary shares of US$1.00 each, with each share carrying one right to vote and with no shares held in treasury.

The above figure of 60,735,104 may be used by shareholders as the denominator for the calculations by which they could determine if they are required to notify their interest in, or a change to their interest in, Chi-Med under the Financial Conduct Authority’s Disclosure Rules and Transparency Rules.

For illustrative purposes only, the 60,735,104 ordinary shares would be equivalent to 60,735,104 CREST depositary interests (each equating to one ordinary share) which are traded on AIM or, if the CREST depositary interests were converted in their entirety, equivalent to 121,470,208 American depositary shares (each equating to one-half of one ordinary share) which are traded on Nasdaq.

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.

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: Thursday, April 27, 2017: Hutchison China MediTech Limited (“Chi-Med”) (AIM/Nasdaq: HCM) today announces that all ordinary resolutions and special resolutions put to its Annual General Meeting (“AGM”) held on April 27, 2017 were duly passed.  The poll results of the resolutions were as follows:

As at the date of the AGM, the number of issued shares of Chi-Med was 60,726,979, which was the total number of shares entitling the holders to attend and vote on the ordinary resolutions and special resolutions proposed at the AGM.

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.

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

2017 年4 月7 日：和黃醫藥在2017 年4 月1 日至5 日於美國華盛頓舉行的美國癌症研究協會(AACR) 年會上公佈了呋喹替尼和索凡替尼的臨床前數據。呋喹替尼和索凡替尼目前都在以多種癌症為適應症的III 期臨床試驗中進行評估。

呋喹替尼是一種高選擇性口服血管細胞內皮生長因子受體（VEGFR）抑製劑，耐受性良好，可與其他癌症療法聯合使用。和黃醫藥將於2017年中完成向中國國家食品藥品監督管理總局遞交呋喹替尼的新藥上市申請。呋喹替尼目前由和黃醫藥和美國禮來在中國范圍內合作開發。

索凡替尼是一種新型口服抗血管生成免疫激酶抑製劑，能夠有效地抑制與VEGFR, FGFR與CSF-1R靶點相關的酪氨酸激酶活性，這三種酪氨酸激酶受體參與了腫瘤新生血管的生成以及免疫逃逸。索凡替尼現有兩項治療神經內分泌瘤的III期臨床研究正在中國展開。

公佈內容如下：

更多關於AACR的信息可參見aacr.org。

摘要

在臨床前腫瘤模型中評估高選擇性口服VEGFR 抑製劑呋喹替尼與其他靶向療法或免疫檢查點抑製劑聯合使用的療效

作者：任永欣，孫巧玲，龍靜雯,范士明，湯仁想, 張煒,葛雪蕾,唐建興,王林芳,石東霞, 陳宏博,程敏,青衛國，蘇慰國

靶向腫瘤血管生成，腫瘤驅動基因改變和腫瘤免疫逃逸的各種療法在提高總生存期（“OS”）方面取得了巨大進步。但如果靶向腫瘤發生的單一機制，療效可能受限且耐藥性往往會快速產生。因此，根據腫瘤特徵探索各療法之間的合理組合是具有研究價值的方向。呋喹替尼是一種高選擇性口服VEGFR抑製劑，目前正在進行分別以非小細胞肺癌和結直腸癌為適應症的III期臨床試驗。我們在這里報告了在臨床前動物腫瘤模型中呋喹替尼聯合其他腫瘤療法靶向腫瘤驅動基因的改變（如“ 表皮生長因子受體”（“ EGFR”）和間充質生長因子受體（“c-MET”）或伴有免疫檢查點）的抗腫瘤療效。

在伴有EGFR激活（例如激活突變、基因擴增或蛋白質過度表達）的非小細胞肺癌異種移植模型中，發現呋喹替尼聯合一種EGFR酪氨酸激酶抑製劑如吉非替尼或西利替尼（HMPL-309）的療法比這兩種藥物的獨立單一療法更有效。例如，在攜帶EGFR外顯子19缺失的PC-9皮下腫瘤模型中，單獨使用2mg / kg的呋喹替尼和5mg / kg的吉非替尼治療產生的腫瘤生長抑制率（“TGI”）為58％和63％，而聯合用藥的TGI 為100％，並且在使用聯合用藥治療的16隻小鼠中有11只觀察到腫瘤消退。

在衍生自肺癌或腎細胞癌的具有c-MET活化（擴增或過表達）的多種移植動物模型中，呋喹替尼聯合c-MET抑製劑沃利替尼（AZD6094，HMPL -504）治療的方法也顯著提高了腫瘤生長抑制率。藥效研究結束時，用免疫組織化學和免疫印跡法分析了腫瘤組織中的CD31和EGFR，c-MET，蛋白激酶B（AKT）和細胞外信號調節激酶（ERK）的磷酸化情況。結果表明，聯合療法中增強的抗腫瘤作用可歸因於對腫瘤細胞的信號通道（EGFR或c-MET）傳導的阻斷和腫瘤微環境中對VEGFR抑制的協同作用。

由血管內皮生長因子（“VEGF”）誘導的免疫抑制檢查點的上調是腫瘤細胞逃避免疫監視的重要機制之一。在同基因鼠類腫瘤模型中，與單獨使用呋喹替尼或單獨使用抗程序性死亡配體1（“PD-L1”）抗體相比，聯合使用呋喹替尼和抗PD -L1抗體顯示出更佳的抗腫瘤效果。探究聯合用藥作用機制的研究正在進行中。

以上所述與呋喹替尼聯合用藥的療法均耐受良好。在這些模型中所觀察到的藥效結果顯示對腫瘤血管生成和腫瘤細胞信號傳導或免疫逃逸的同時阻斷有望成為提高療效的一種重要途徑。

一種新型的靶向VEGFR，FGFR1 和CSF-1R 激酶的血管免疫激酶抑製劑— 索凡替尼的臨床前評估

作者：周京紅,倪俊,程敏, 楊娜,梁軍清,葛亮, 張煒,唐建興, 孫巧玲,李富,胡佳,石東霞, 陳宏博, 龍靜雯, 孫軍恩,尹芳,葛雪蕾, 賈紅,周峰,任永欣,青衛國，蘇慰國

VEGFR和FGFR信號通路均可介導腫瘤血管生成。CSF-1R 對巨噬細胞的功能起到關鍵作用。最近，VEGFR，FGFR在調節T 細胞，腫瘤相關巨噬細胞（“TAM”）和骨髓來源的抑制細胞的過程中加劇了腫瘤免疫逃逸的作用已得到驗證。因此，通過同時靶向VEGFR，FGFR和CSF-1R激酶來阻斷腫瘤血管生成和腫瘤免疫逃逸有望成為抗癌治療的一種嶄新途徑。

這項報告是索凡替尼（HMPL-012）的臨床前研究，該化合物是一種針對VEGFR，FGFR1和CSF-1R的高選擇性小分子酪氨酸激酶抑製劑。索凡替尼可抑制VEGFR1,2和3，FGFR1和CSF-1R激酶（IC _50s 值範圍為1〜24nM）並且高效阻斷HEK293 ^KDR 細胞中VEGF 誘導的VEGFR2磷酸化和RAW264.7 細胞中集落刺激因子-1（CSF-1R）誘導的磷酸化（IC ₅₀ 值分別為2和79 nM ）。

索凡替尼也減緩VEGF或FGF 誘導的HUVEC 細胞增殖（IC ₅₀ < 50 nM ）。在動物研究中，單劑量口服的索凡替尼以暴露量依賴的方式抑制裸鼠肺組織中VEGF 誘導的VEGFR2磷酸化。此外，給藥後24小時血漿中FGF23水平升高表明FGFR信號傳導得到了有效抑制。

索凡替尼在多種人體異種移植模型中表現出高效的腫瘤生長抑製作用，並能顯著降低CD31表達，表明其通過VEGFR和FGFR信號傳導對腫瘤血管生成具有強烈的抑制作用。在同基因鼠結腸癌模型CT-26中，索凡替尼單次用藥就顯示出中度抑制腫瘤生長的作用。通過流式細胞技術和免疫組織化學分析，顯示CD8 + T 細胞的增多和腫瘤組織中腫瘤相關巨噬細胞（CD163 +或F4 / 80 + CD11b + CD45 +）和CSF -1R + 腫瘤相關巨噬細胞（TAMs）的明顯降低，表明索凡替尼對CSF-1R通路具有強烈抑製作用。

有趣的是，索凡替尼與PD-L1抗體的組合獲得了更強的抗腫瘤效果。這些結果表明索凡替尼具有很強的調節血管生成和腫瘤免疫作用。

綜上所述，索凡替尼是一種新型口服血管免疫激酶抑製劑，能夠有效地抑制與VEGFR, FGFR與CSF-1R靶點相關的酪氨酸激酶活性，從而同時阻斷腫瘤新生血管的生成以及免疫逃逸。索凡替尼的這一特性使其有可能與各種癌症的檢查點抑製劑組合進行探索研究。索凡替尼現有多項臨床試驗正在進行中，包括兩項以神經內分泌瘤為適應症的III期臨床試驗。

關於呋喹替尼

呋喹替尼是一種新型的高選擇性小分子候選藥物，臨床研究證實：通過一日一次的口服劑量即可有效的抑制血管內皮生長因子受體（VEGFR），且脫靶毒性低於其他靶向療法。癌症進入到晚期，腫瘤會分泌大量的蛋白配體-血管內皮生長因子(VEGF)，以促進腫瘤組織周圍過度的脈管系統的生成(血管生成)，為腫瘤細胞的生長提供更多的血流，氧氣和營養。VEGF和其受體VEGFR在腫瘤的血管生成中起到了至關重要的作用，因此，對VEGF/VEGFR相關通路的抑制就成為了阻斷新生血管形成，防止腫瘤增長和侵入的一種重要的治療策略。

根據此前的合作協議，呋喹替尼由和黃醫藥和美國禮來在中國范圍內合作開發。2017年3月初，合作的雙方共同宣布呋喹替尼以結直腸癌為適應症的III期臨床試驗“FRESCO”的研究結果，參與該研究的416名受試者為至少經過2 輪化療／治療　（包括奧沙利鉑和氟尿嘧啶類藥物及伊立替康）失敗的轉移性結直腸癌患者。

“ FRESCO”研究的意向治療人群（ITT）接受了呋喹替尼聯合最佳支持治療(BSC) 對比安慰劑聯合最佳支持治療，結果顯示總生存期(OS) 獲得了具有臨床和統計學意義的顯著提高，成功達到了這一主要終點。此外，該試驗也成功達到了無進展生存期(PFS) 這一關鍵的次要終點，且研究過程中未出現新的或超出預期的不良安全事件。和黃醫藥將於近期完成向國家食品藥品監督管理總局遞交呋喹替尼的新藥上市申請。詳細的研究結果現正在進一步分析之中，並有望公佈於2017年年中舉行的學術大會上。

此外，呋喹替尼以非小細胞肺癌為適應症的III期臨床試驗被命名為“FALUCA”，目前正在中國展開研究，另有一項II期臨床試驗以呋喹替尼聯合易瑞沙（吉非替尼）治療一線晚期或轉移性非小細胞肺癌也正在進行中。與紫杉醇聯合用藥治療胃癌的中國III期臨床研究，在美國的數項新研究，以及與其他腫瘤藥物聯合用藥的多項探索性研究也正在計劃中，將於今後逐漸展開。

關於索凡替尼

索凡替尼是一種新型口服血管免疫激酶抑製劑，能夠有效地抑制與VEGFR, FGFR與CSF-1R靶點相關的酪氨酸激酶活性，這三種酪氨酸激酶受體參與了腫瘤新生血管的生成以及免疫逃逸。通過抑制VEGFR信號通路能夠阻斷腫瘤組織周圍過度的脈管系統的生成（血管生成），從而切斷了腫瘤快速增長所需營養及氧氣的供給。抗VEGFR 療法可能會加劇FGFR信號通路的異常激活，從而導致因腫瘤增長而產生的疾病進展，腫瘤周圍的血管生成以及髓系衍生抑制細胞的形成。抑制CSF-1R信號通路可阻斷腫瘤相關巨噬細胞的活化，從而調控巨噬細胞參與抑製針對腫瘤的免疫應答。

索凡替尼現有六項臨床試驗正在美國和中國展開，包括以神經內分泌瘤（SANET-p, SANET-ep及SANET-1）為適應症的兩項III期臨床研究和一項II期臨床研究，以甲狀腺癌為適應症的一項II期臨床研究及以膽管癌為適應症的一項II期臨床研究。

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.

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 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.