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：和黄医药在2017年4月1日至5日于美国华盛顿举行的美国癌症研究协会(AACR)年会上公布了呋喹替尼和索凡替尼的临床前数据。呋喹替尼和索凡替尼目前都在以多种癌症为适应症的III期临床试验中进行评估。

呋喹替尼是一种高选择性口服血管细胞内皮生长因子受体（VEGFR）抑制剂，耐受性良好，可与其他癌症疗法联合使用。和黄医药将于2017年中完成向中国国家食品药品监督管理总局递交呋喹替尼的新药上市申请。呋喹替尼目前由和黄医药和美国礼来在中国范围内合作开发。

索凡替尼是一种新型口服抗血管生成免疫激酶抑制剂，能够有效地抑制与VEGFR, FGFR与CSF-1R靶点相关的酪氨酸激酶活性，这三种酪氨酸激酶受体参与了肿瘤新生血管的生成以及免疫逃逸。索凡替尼现有两项治疗神经内分泌瘤的III期临床研究正在中国展开。

公布内容如下：

更多关于AACR的信息可参见aacr.org。

摘要

在临床前肿瘤模型中评估高选择性口服VEGFR抑制剂呋喹替尼与其他靶向疗法或免疫检查点抑制剂联合使用的疗效

作者：任永欣， 孙巧玲，  龙静雯, 范士明， 汤仁想, 张炜, 葛雪蕾, 唐建兴, 王林芳, 石东霞, 陈宏博, 程敏,青卫国，苏慰国

靶向肿瘤血管生成，肿瘤驱动基因改变和肿瘤免疫逃逸的各种疗法在提高总生存期（“OS”）方面取得了巨大进步。但如果靶向肿瘤发生的单一机制，疗效可能受限且耐药性往往会快速产生。因此，根据肿瘤特征探索各疗法之间的合理组合是具有研究价值的方向。呋喹替尼是一种高选择性口服VEGFR抑制剂，目前正在进行分别以非小细胞肺癌和结直肠癌为适应症的III期临床试验。我们在这里报告了在临床前动物肿瘤模型中呋喹替尼联合其他肿瘤疗法靶向肿瘤驱动基因的改变（如“表皮生长因子受体”（“EGFR”）和间充质生长因子受体（“c-MET”）或伴有免疫检查点）的抗肿瘤疗效。

在伴有EGFR激活（例如激活突变、基因扩增或蛋白质过度表达）的非小细胞肺癌异种移植模型中，发现呋喹替尼联合一种EGFR酪氨酸激酶抑制剂如吉非替尼或西利替尼（HMPL-309）的疗法比这两种药物的独立单一疗法更有效。例如，在携带EGFR外显子19缺失的PC-9皮下肿瘤模型中，单独使用2mg / kg的呋喹替尼和5mg / kg的吉非替尼治疗产生的肿瘤生长抑制率（“TGI”）为58％和63％，而联合用药的TGI为100％，并且在使用联合用药治疗的16只小鼠中有11只观察到肿瘤消退。

在衍生自肺癌或肾细胞癌的具有c-MET活化（扩增或过表达）的多种移植动物模型中，呋喹替尼联合c-MET抑制剂沃利替尼（AZD6094，HMPL-504）治疗的方法也显著提高了肿瘤生长抑制率。药效研究结束时，用免疫组织化学和免疫印迹法分析了 肿瘤组织中的CD31和EGFR，c-MET，蛋白激酶B（AKT）和细胞外信号调节激酶（ERK）的磷酸化情况。结果表明，联合疗法中增强的抗肿瘤作用可归因于对肿瘤细胞的信号通道（EGFR或c-MET）传导的阻断和肿瘤微环境中对VEGFR抑制的协同作用。

由血管内皮生长因子（“VEGF”）诱导的免疫抑制检查点的上调是肿瘤细胞逃避免疫监视的重要机制之一。在同基因鼠类肿瘤模型中，与单独使用呋喹替尼或单独使用抗程序性死亡配体1（“PD-L1”）抗体相比，联合使用呋喹替尼和抗PD-L1抗体显示出更佳的抗肿瘤效果。探究联合用药作用机制的研究正在进行中。

以上所述与呋喹替尼联合用药的疗法均耐受良好。在这些模型中所观察到的药效结果显示对肿瘤血管生成和肿瘤细胞信号传导或免疫逃逸的同时阻断有望成为提高疗效的一种重要途径。

一种新型的靶向VEGFR，FGFR1和CSF-1R激酶的血管免疫激酶抑制剂—索凡替尼的临床前评估

作者：周京红, 倪俊, 程敏, 杨娜, 梁军清, 葛亮, 张炜, 唐建兴, 孙巧玲, 李富, 胡佳, 石东霞, 陈宏博, 龙静雯, 孙军恩, 尹芳, 葛雪蕾, 贾红, 周峰, 任永欣, 青卫国，苏慰国

VEGFR和FGFR信号通路均可介导肿瘤血管生成。 CSF-1R对巨噬细胞的功能起到关键作用。 最近，VEGFR，FGFR在调节T细胞，肿瘤相关巨噬细胞（“TAM”）和骨髓来源的抑制细胞的过程中加剧了肿瘤免疫逃逸的作用已得到验证。 因此，通过同时靶向VEGFR，FGFR和CSF-1R激酶来阻断肿瘤血管生成和肿瘤免疫逃逸有望成为抗癌治疗的一种崭新途径。

这项报告是索凡替尼（HMPL-012）的临床前研究，该化合物是一种针对VEGFR，FGFR1和CSF-1R的高选择性小分子酪氨酸激酶抑制剂。 索凡替尼可抑制VEGFR1,2和3，FGFR1和CSF-1R激酶（IC_50s值范围为1〜24nM）并且高效阻断HEK293^KDR细胞中VEGF诱导的VEGFR2磷酸化和RAW264.7细胞中集落刺激因子-1（CSF-1R）诱导的磷酸化（IC₅₀值分别为2和79 nM）。

索凡替尼也减缓VEGF或FGF诱导的HUVEC细胞增殖（IC₅₀ < 50 nM）。 在动物研究中，单剂量口服的索凡替尼以暴露量依赖的方式抑制裸鼠肺组织中VEGF诱导的VEGFR2磷酸化。 此外，给药后24小时血浆中FGF23水平升高表明FGFR信号传导得到了有效抑制。

索凡替尼在多种人体异种移植模型中表现出高效的肿瘤生长抑制作用，并能显著降低CD31表达，表明其通过VEGFR和FGFR信号传导对肿瘤血管生成具有强烈的抑制作用。 在同基因鼠结肠癌模型CT-26中，索凡替尼单次用药就显示出中度抑制肿瘤生长的作用。 通过流式细胞技术和免疫组织化学分析，显示CD8 + T细胞的增多和肿瘤组织中肿瘤相关巨噬细胞（CD163 +或F4 / 80 + CD11b + CD45 +）和CSF-1R + 肿瘤相关巨噬细胞（TAMs）的明显降低，表明索凡替尼对CSF-1R通路具有强烈抑制作用。

有趣的是，索凡替尼与PD-L1抗体的组合获得了更强的抗肿瘤效果。 这些结果表明索凡替尼具有很强的调节血管生成和肿瘤免疫作用。

综上所述，索凡替尼是一种新型口服血管免疫激酶抑制剂，能够有效地抑制与VEGFR, FGFR与CSF-1R靶点相关的酪氨酸激酶活性，从而同时阻断肿瘤新生血管的生成以及免疫逃逸。索凡替尼的这一特性使其有可能与各种癌症的检查点抑制剂组合进行探索研究。索凡替尼现有多项临床试验正在进行中，包括两项以神经内分泌瘤为适应症的III期临床试验。

关于呋喹替尼

呋喹替尼是一种新型的高选择性小分子候选药物，临床研究证实：通过一日一次的口服剂量即可有效的抑制血管内皮生长因子受体（VEGFR），且脱靶毒性低于其他靶向疗法。癌症进入到晚期，肿瘤会分泌大量的蛋白配体-血管内皮生长因子(VEGF)，以促进肿瘤组织周围过度的脉管系统的生成(血管生成)，为肿瘤细胞的生长提供更多的血流，氧气和营养。VEGF和其受体VEGFR在肿瘤的血管生成中起到了至关重要的作用，因此，对VEGF/VEGFR相关通路的抑制就成为了阻断新生血管形成，防止肿瘤增长和侵入的一种重要的治疗策略。

根据此前的合作协议，呋喹替尼由和黄医药和美国礼来在中国范围内合作开发。2017年3月初，合作的双方共同宣布呋喹替尼以结直肠癌为适应症的III期临床试验“FRESCO”的研究结果，参与该研究的416名受试者为至少经过2轮化疗／治疗　（包括奥沙利铂和氟尿嘧啶类药物及伊立替康）失败的转移性结直肠癌患者。

“FRESCO”研究的意向治疗人群（ITT）接受了呋喹替尼联合最佳支持治疗(BSC)对比安慰剂联合最佳支持治疗，结果显示总生存期(OS)获得了具有临床和统计学意义的显著提高，成功达到了这一主要终点。此外，该试验也成功达到了无进展生存期(PFS)这一关键的次要终点，且研究过程中未出现新的或超出预期的不良安全事件。和黄医药将于近期完成向国家食品药品监督管理总局递交呋喹替尼的新药上市申请。详细的研究结果现正在进一步分析之中，并有望公布于2017年年中举行的学术大会上。

此外，呋喹替尼以非小细胞肺癌为适应症的III期临床试验被命名为“FALUCA”，目前正在中国展开研究，另有一项II期临床试验以呋喹替尼联合易瑞沙（吉非替尼）治疗一线晚期或转移性非小细胞肺癌也正在进行中。与紫杉醇联合用药治疗胃癌的中国III期临床研究，在美国的数项新研究，以及与其他肿瘤药物联合用药的多项探索性研究也正在计划中，将于今后逐渐展开。

关于索凡替尼

索凡替尼是一种新型口服血管免疫激酶抑制剂，能够有效地抑制与VEGFR, FGFR与CSF-1R靶点相关的酪氨酸激酶活性，这三种酪氨酸激酶受体参与了肿瘤新生血管的生成以及免疫逃逸。通过抑制VEGFR信号通路能够阻断肿瘤组织周围过度的脉管系统的生成（血管生成），从而切断了肿瘤快速增长所需营养及氧气的供给。抗VEGFR疗法可能会加剧FGFR信号通路的异常激活，从而导致因肿瘤增长而产生的疾病进展，肿瘤周围的血管生成以及髓系衍生抑制细胞的形成。抑制CSF-1R信号通路可阻断肿瘤相关巨噬细胞的活化，从而调控巨噬细胞参与抑制针对肿瘤的免疫应答。

索凡替尼现有六项临床试验正在美国和中国展开，包括以神经内分泌瘤（SANET-p, SANET-ep及SANET-1）为适应症的两项III期临床研究和一项II期临床研究，以甲状腺癌为适应症的一项II期临床研究及以胆管癌为适应症的一项II期临床研究。

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.